2-Aminopyridine compounds and use thereof as drugs

ABSTRACT

The present invention provides 2-aminopyridine compound having an excellent adenosine receptor (A 1 , A 2a , A 2b  receptors) antagonism, which is represented by the following formula:  
                 
 
     (wherein, R 1  represents cyano group, carboxyl group or an optionally substituted carbamoyl group; R 2  represents hydrogen atom, hydroxyl group, an optionally substituted C 1-6  alkoxy group, an optionally substituted C 6-14  aromatic hydrocarbon cyclic group or an optionally substituted 5- to 14-membered aromatic heterocyclic group; and R 3  and R 4  are the same as or different from each other and each represents a C 6-14  aromatic hydrocarbon cyclic group, a 5- to 14-membered non-aromatic heterocyclic group or a 5- to 14-membered aromatic heterocyclic group which may be substituted, respectively) or a salt thereof.

TECHNICAL FIELD The present invention relates to a novel 2-aminopyridinecompound, a process for producing it, and use thereof as a medicament.PRIOR ART

[0001] Adenosine is an important regulatory factor involved in variousintracellular metabolisms such as regulation of energy levels and cAMPlevels in the living body, opening and closing calcium channels, andinflow of calcium ions into cells, and can exhibit its physiologicalactivity by interaction with G protein-conjugated receptors on thesurface of a cell. Adenosine receptors were at first classified into 2classes, that is, A₁ l receptor and A₂ receptor on the basis of theirparticipation in adenylate cyclase (J. Neurochem., 33, 999-1003 (1979)),and thereafter, the A₂ receptor was classified into 2 subtypes, that is,A_(2A) and A_(2B) on the basis of their affinity for NECA and CGS-21680(Mol. Pharmacol., 29, 331-346 (1986); J. Neurochem., 55, 1763-1771(1990)) which are adenosine A₂ receptor agonists. Thus, 4 receptorsubtypes, A₁, A₂ (A_(2A), A_(2A)) and A₃, have been identified untilnow. The A₁ receptor is a protein conjugated with G_(i/o) familyprotein. By binding of ligands, it inhibits adenylate cyclase tosuppress CAMP levels and activates phospholipase C (PLC) to promoteproduction of inositol-1,4,5-triphosphate (IP₃) and release ofintracellular calcium ions. It is known that similar to the A₁ receptor,the A₃ receptor is a receptor suppressing cAMP levels and activating PLCto promote production of IP₃ and release of intracellular calcium ions.On the other hand, the A_(2A) and A_(2B) receptors are those activatingadenylate cyclase and promoting production of cAMP levels. It is alsoreported that A_(2B) is conjugated with PLC via G_(q)/G₁₁ protein, andpromotes production of IP₃ levels and inflow of calcium ions into cells(Clin. Invest., 96, 1979-1986 (1995)). These subtypes are different fromone another in their distribution in tissues; that is, the A₁ receptoroccurs relatively abundantly in the heart, aorta, bladder, etc., theA_(2A) receptor in the eyeballs, skeletal muscles, etc., and the A₃receptor in the spleen, uterus, prostate, etc., while the A_(2B)receptor occurs relatively abundantly in proximity to the largeintestine and in the eyeballs, lung, uterus and bladder (Br. J.Pharmacol., 118, 1461-1468 (1996)). The reason that adenosine receptorsubtypes can exhibit their inherent functions is attributable to adifference in their distribution in tissues, a difference in topicaladenosine levels and a difference in affinity of each subtype forligands. Adenosine is involved in various physiological functions suchas platelet agglutination, heartbeats, contraction of smooth muscles,inflammations, release of neurotransmitters, neurotransmission, releaseof hormones, cellular differentiation, growth of cells, death of cells,biosynthesis of DNA, etc., thus suggesting the relationship of adenosinewith diseases in the neutral nerves, cardiovascular diseases,inflammatory diseases, diseases in the respiratory organs, immunediseases, etc., so usefulness of adenosine receptor agonists/antagonistsagainst these diseases is expected. On one hand, important reports havebeen made in recent years on the relationship between the adenosine A₂receptor and the intestinal tracts. For example, it is reported that arelaxing action on colon longitudinal muscles is mediated by A₂ receptor(Naunyn-Schmiedeberg's Arch. Pharmacol., 359, 140-146(1999)), and thatthe relaxing action of adenosine on contraction of guinea pig distantcolon longitudinal muscles is mediated by A₁ receptor and A_(2b)receptor in longitudinal muscles (Br. J. Pharmacol., 129, 871-876(2000)). Heretofore, antagonists for adenosine receptors, particularlyfor adenosine A₂ receptor, have been noted to be useful as an agent fortreating or preventing diabetes, diabetic complications, diabeticretinopathy, obesity or asthma, and expected to be useful as ahypoglycemic agent, an improving agent for impaired glucose tolerance, apotentiating agent for insulin sensitivity, a hypotensive agent, adiuretic, a therapeutic agent for osteoporosis, an anti-Parkinson'sdisease agent, an anti-Alzheimer's disease agent, a therapeutic agentfor inflammatory intestinal diseases or a therapeutic agent for Crohn'sdisease, etc.

[0002] For example, there are following reports on compounds having anantagonistic action particularly on A_(2B) receptor.

[0003] (1) Compounds represented by the formulae:

[0004] 3-n-Propylxanthine, Theophylline, Caffeine,

[0005] 1,3-Dipropylxanthine, Enprophylline, 1-Methyl-3-isobutylxanthine,

[0006] Paraxanthine, 8-Phenyltheophylline, 1,3-Diethyl-8-phenylxanthine,

[0007] 1,3-Dimethyl-8- Alloxazine, (p-sulfophenyl)xanthine,

[0008] 8-[4-][Methyl-(2-dimethylaminoethyl)-amino]sulfonylphenyl-1,3-dipropylxanthine,

[0009] 1,3-Dipropyl-8-(p-sulfophenyl)xanthine,

[0010]8-[4-[[[[(2-Aminoethyl)amino]carbonyl]methyl]oxy]phenyl]-1,3-dipropylxanthine,

[0011] 2,4-Dioxobenzo[g]pteridine

[0012] (2) Purine derivatives represented by the formula:

[0013] (wherein R¹ means (1) the formula:

[0014] (wherein X means hydrogen atom, hydroxyl group, an optionallysubstituted lower alkyl group, an optionally substituted lower alkoxygroup etc.; and R⁵ and R⁶ are the same as or different from each otherand each means hydrogen atom, an optionally substituted lower alkylgroup, an optionally substituted saturated or unsaturated C₃₋₈cycloalkyl group etc.) or (2) a 5- to 6-membered aromatic ring which mayhave a substituent group and a hetero atom; W means the formula—CH₂CH₂—, —CH═CH— or —C≡C—; R² means an amino group which may besubstituted with an optionally substituted lower alkyl group etc., etc.;R³ means an optionally substituted C₃₋₈ cycloalkyl group, an optionallysubstituted aryl group, etc.; and R⁴ means an optionally substitutedlower alkyl group etc.), or a pharmacologically acceptable salt thereofor a hydrate of them (JP-A 11-263789).

[0015] (3) Purine derivatives represented by the formula:

[0016] (wherein R¹ represents hydrogen atom, hydroxyl group, a halogenatom, an optionally substituted C₁₋₈ alkyl group, etc.; R² represents anamino group which may be substituted with a C₁₋₈ alkyl group, etc.; R³represents a C₃₋₈ alkynyl group which may be substituted with a halogenatom, hydroxyl group or a C₁₋₄ alkyl group, etc.; Ar represents anoptionally substituted aryl group, an optionally substituted heteroarylgroup, etc.; and Q and W are the same as or different from each otherand each represents N or CH), a pharmacologically acceptable saltthereof or a hydrate of them.

[0017] (4) A_(2B) receptor antagonists described in Drug DevelopmentResearch, 48: 95-103 (1999) and J. Med. Chem., 43: 1165-1172 (2000).

[0018] On one hand, as pyridine compounds, for example, there arereports relating to 5,6-aromatic substituted pyridine compound in WO96/24584, U.S. Pat. NO. 5,686,470 and U.S. Pat. No. 5,916,905. Further,in DE-A1 4117802, there are reports relating to2-amino-3-pyridinecarbonitrile, and relating to the compound in whichthe 4-, 5- and 6-positions of the pyridine ring are substituted withphenyl groups. However, the relationship of these compounds with anadenosine receptor is not described or suggested, and is not known atall.

[0019] As described above, those compounds having an antagonism to anadenosine receptor, particularly an antagonism to an adenosine A₂receptor (especially A_(2b) receptor), are expected to exhibit anexcellent action as pharmaceutical preparations and desired to beprovided. However, those compounds having an excellent antagonism to anadenosine receptor and also acting effectively as a medicament havenever been found. Accordingly, the object of the present invention is tosearch for, and find, the receptor inhibiting compound which is usefulas an agent for treating or preventing a disease to which an adenosinereceptor (particularly A₂ receptor, A_(2b) receptor) relates.

DISCLOSURE OF THE INVENTION

[0020] Considering the above-described circumstances, the presentinventors made intensive study. As a result, they have succeeded for thefirst time in synthesizing a compound represented by the formula:

[0021] (wherein R¹ represents cyano group, carboxyl group or anoptionally substituted carbamoyl group; R² represents hydrogen atom,hydroxyl group, an optionally substituted C₁₋₆ alkoxy group, anoptionally substituted C₆₋₁₄ aromatic hydrocarbon cyclic group or anoptionally substituted 5- to 14-membered aromatic heterocyclic group;and R³ and R⁴ are the same as or different from each other and eachrepresents a C₃₋₈ cycloalkyl group, a C₃₋₈ cycloalkenyl group, a C₆₋₁₄aromatic hydrocarbon cyclic group, a 5- to 14-membered non-aromaticheterocyclic group or a 5- to 14-membered aromatic heterocyclic groupwhich may have a substituent group, respectively, provided that thecases where (1) R¹ is cyano group, R² is 4-bromo-2-thienyl group, R³ is3,4-dimethoxyphenyl group and R⁴ is 2-thienyl group, (2) R¹ is cyanogroup, R² is hydrogen atom, and each of R³ and R⁴ is phenyl group, (3)R¹ is cyano group, R² is 4-chlorophenyl group, R³ is phenyl group and R⁴is 4-(3,4-dichlorophenyl)-1-oxo-2(1H)-phthalazinyl group, (4) R¹ iscyano group, R² is hydrogen atom, R³ is 4-pyridyl group and R⁴ is1-piperazinyl group, (5) R¹ is cyano group, R² is hydrogen atom, R³ is4-pyridyl group and R⁴ is a 1-pyridyl group, (6) R¹ is cyano group, R²is hydrogen atom, R³ is 4-pyridyl group and R⁴ is4-diphenylmethyl-1-piperazinyl group, (7) R¹ is cyano group, R² ishydrogen atom, R³ is 4-pyridyl group and R⁴ is 4-morpholinyl group, (8)R¹ is cyano group, R² is 4-methylphenyl group, and each of R³ and R⁴ isphenyl group and (9) R¹is cyano group, and each of R², R³ and R⁴ isphenyl group are excluded) or a salt thereof, and they unexpectedlyfound that the compound and a salt thereof have an excellentantagonistic action on adenosine A₂ receptor, particularly A_(2B)receptor. As a result of further intensive study, they found that thecompound or a salt thereof is useful not only as an agent for treating,preventing or improving a disease to which an adenosine receptor,particularly A₂ receptor, especially A_(2B) receptor, relates, forexample, constipation, irritable bowel syndrome, constipationaccompanying irritable bowel syndrome, organic constipation,constipation accompanying enteroparalytic ileus, constipationaccompanying congenital digestive tract dysfunction, constipationaccompanying ileus, diabetes, diabetic complications, diabeticretinopathy, obesity, asthma etc., but also useful as a hypoglycemicagent, an improving agent for impaired glucose tolerance, a potentiatingagent for insulin sensitivity, hypotensive agent, a diuretic, atherapeutic agent for osteoporosis, an anti-Parkinson's disease agent,an anti-Alzheimer's disease agent, a therapeutic agent for inflammatoryintestinal diseases, a therapeutic agent for Crohn's disease etc., andthus completed the present invention.

[0022] That is, the present invention relates to (1) a compoundrepresented by the above formula (I) or a salt thereof; (2) the compoundaccording to the above-mentioned (1) or a salt thereof, in which R¹ iscyano group; (3) the compound according to the above-mentioned (1) or asalt thereof, in which R¹ is a carbamoyl group represented by theformula:

[0023] (wherein R⁵ and R⁶ are the same as or different from each otherand each represents hydrogen atom, an optionally substituted C₁₋₆ alkylgroup, an optionally substituted C₂₋₆ alkenyl group, an optionallysubstituted C₂₋₆ alkynyl group, an optionally substituted C₆₋₁₄ aromatichydrocarbon cyclic group or an optionally substituted 5- to 14-memberedaromatic heterocyclic group); (4) the compound according to theabove-mentioned (1) or a salt thereof, in which R² is a C₆₋₁₄ aromatichydrocarbon cyclic group or 5- to 14-membered aromatic heterocyclicgroup, each of which may have a substituent group; (5) the compoundaccording to the above-mentioned (1) or a salt thereof, in which R² is aphenyl group, naphthyl group, pyridyl group, thienyl group or furylgroup, each of which may have a substituent group; (6) the compoundaccording to the above-mentioned (1) or a salt thereof, in which R² is aphenyl group which may be substituted with a halogen atom; (7) thecompound according to the above-mentioned (1) or a salt thereof, inwhich R² is hydrogen atom; (8) the compound according to theabove-mentioned (1) or a salt thereof, in which R³ and R⁴ are the sameas or different from each other and each represents a C₆₋₁₄ aromatichydrocarbon cyclic group or a 5- to 14-membered aromatic heterocyclicgroup, each of which may have a substituent group; (9) the compoundaccording to the above-mentioned (1) or a salt thereof, in which R³ andR⁴ are the same as or different from each other and each represents aphenyl group, pyrrolyl group, pyridinyl group, pyridazinyl group,pyrimidinyl group, pyrazinyl group, thienyl group, thiazolyl group,furyl group, naphthyl group, quinolinyl group, isoquinolinyl group,phthalazinyl group, naphthyridinyl group, indolyl group or isoindolylgroup, each of which may have a substituent group; (10) the compoundaccording to the above-mentioned (1) or a salt thereof, in which each ofR³ and R⁴ represents a phenyl group, pyridyl group, thienyl group orfuryl group which may have a substituent group, respectively; (11) thecompound according to the above-mentioned (1) or salts thereof, whereinR³ and/or R⁴ represent a 5- to 14-membered non-aromatic heterocyclicgroup, a C₆₋₁₄ aromatic hydrocarbon cyclic group or a 5- to 14-memberedaromatic heterocyclic group, each of which may be substituted with atleast one group selected from the following substituent group a (theabove-mentioned “substituent group a” is a group consisting of (1) ahydroxyl group, (2) a halogen atom, (3) a nitrile group, (4) a nitrogroup, (5) a C₁₋₆ alkyl group, C₂₋₆ alkenyl group or C₂₋₆ alkynyl group,each of which may be substituted with at least one group selected from(i) hydroxyl group, (ii) nitrile group, (iii) halogen atom, (iv) C₁₋₆alkylamino group, (v) di(C₁₋₆ alkyl)amino group, (vi) C₂₋₆ alkenylaminogroup, (vii) di(C₂₋₆ alkenyl)amino group, (viii) C₂₋₆ alkynylaminogroup, (ix) di(C₂₋₆ alkynyl)amino group, (x) N-C₁₋₆ alkyl-N-C₂₋₆alkenylamino group, (xi) N-C₁₋₆ alkyl-N-C₂₋₆ alkynylamino group, (xii)N-C₂₋₆ alkenyl-N-C₂₋₆ alkynylamino group, (xiii) aralkyloxy group, (xiv)TBDMS oxy group, (xv) C₁₋₆ alkylsulfonylamino group, (xvi) C₁₋₆alkylcarbonyloxy group, (xvii) C₂₋₆ alkenylcarbonyloxy group, (xviii)C₂₋₆ alkynylcarbonyloxy group, (xix) N-C₁₋₆ alkylcarbamoyl group, (xx)N-C₂₋₆ alkenylcarbamoyl group and (xxi) N-C₁₋₆ alkynylcarbamoyl group,(6) a C₁₋₆ alkoxy group, C₂₋₆ alkenyloxy group or C₂₋₆ alkynyloxy group,each of which may be substituted with at least one group selected from(i) C₁₋₆ alkylamino group, (ii) aralkyloxy group and (iii) hydroxylgroup, (7) a C₁₋₆ alkylthio group, C₂₋₆ alkenylthio group or C₂₋₆alkynylthio group, each of which may be substituted with at least onegroup selected from (i) hydroxyl group, (ii) nitrile group, (iii)halogen atom, (iv) C₁₋₆ alkylamino group, (v) aralkyloxy group, (vi)TBDMS oxy group, (vii) C₁₋₆ alkylsulfonylamino group, (viii) C₁₋₆alkylcarbonyloxy group and (ix) C₁₋₆ alkylcarbamoyl group, (8) acarbonyl group substituted with a group selected from (i) C₁₋₆ alkoxygroup, (ii) amino group, (iii) C₁₋₆ alkylamino group, (iv) di(C₁₋₆alkyl)amino group, (v) C₂₋₆ alkenylamino group, (vi) di (C₂₋₆alkenyl)amino group, (vii) C₂₋₆ alkynylamino group, (vii) di(C₂₋₆alkynyl)amino group, (viii) N-C₁₋₆ alkyl-N-C₂₋₆ alkenylamino group, (ix)N-C₁₋₆ alkyl-N-C₂₋₆ alkynylamino group and (x) N-C₂₋₆ alkenyl-N-C₂₋₆alkynylamino group, (9) an amino group which may be substituted with oneor two groups selected from (i) C₁₋₆ alkyl group, (ii) C₂₋₆ alkenylgroup, (iii) C₂₋₆ alkynyl group, (iv) C₁₋₆ alkylsulfonyl group, (v) C₂₋₆alkenylsulfonyl group, (vi) C₂₋₆ alkynylsulfonyl group, (vii) C₁₋₆alkylcarbonyl group, (viii) C₂₋₆ alkenylcarbonyl group and (ix) C₂₋₆alkynylcarbonyl group, (10) a C₁₋₆ alkylsulfonyl group, (11) a C₂₋₆alkenylsulfonyl group, (12) a C₂₋₆ alkynylsulfonyl group, (13) a C₁₋₆alkylsulfinyl group, (14) a C₂₋₆ alkenylsulfinyl group, (15) a C₂₋₆alkynylsulfinyl group, (16) a formyl group, (17) a C₃₋₈ cycloalkyl groupor C₃₋₈ cycloalkenyl group, each of which may be substituted with atleast one group selected from (i) hydroxyl group, (ii) halogen atom,(iii) nitrile group, (iv) C₁₋₆ alkyl group, (v) C₁₋₆ alkoxy group, (vi)C₁₋₆ alkoxy-C₁₋₆ alkyl group and (vii) aralkyl group, (18) a 5- to14-membered non-aromatic heterocyclic group which may be substitutedwith at least one group selected from (i) hydroxyl group, (ii) halogenatom, (iii) nitrile group, (iv) C₁₋₆ alkyl group, (v) C₁₋₆ alkoxy group,(vi) C₁₋₆ alkoxy-C₁₋₆ alkyl group and (vii) aralkyl group, (19) a C₆₋₁₄aromatic hydrocarbon cyclic group which may be substituted with at leastone group selected from (i) hydroxyl group, (ii) halogen atom, (iii)nitrile group, (iv) C₁₋₆ alkyl group, (v) C₁₋₆ alkoxy group, (vi) C₁₋₆alkoxy-C₁₋₆ alkyl group and (vii) aralkyl group, and (20) a 5-to14-membered aromatic heterocyclic group which may be substituted withat least one group selected from (i) hydroxyl group, (ii) halogen atom,(iii) nitrile group, (iv) C₁₋₆ alkyl group, (v) C₁₋₆ alkoxy group, (vi)C₁₋₆ alkoxy-C₁₋₆ alkyl group and (vii) aralkyl group); (12) the compoundaccording to the above-mentioned (1) or a salt thereof, in which R³and/or R⁴ represent a phenyl group, pyridyl group, thienyl group orfuryl group, each of which may be substituted with at least one groupselected from hydroxyl group, a halogen atom, a C₁₋₆ alkyl group and aC₁₋₆ alkoxy group; (13) the compound according to the above-mentioned(1) or a salt thereof, in which R³ or R⁴ is a 6-oxo-1,6-dihydropyridylgroup which may have a substituent group; (14) the compound according tothe above-mentioned (1) represented by the formula:

[0024] (wherein R¹ represents cyano group, carboxyl group or anoptionally substituted carbamoyl group; R² represents hydrogen atom,hydroxyl group, an optionally substituted C₁₋₆ alkoxy group, anoptionally substituted C₁₋₆ alkylthio group, an optionally substitutedC₆₋₁₄ aromatic hydrocarbon cyclic group or an optionally substituted 5-to 14-membered aromatic heterocyclic group; R⁷ represents a groupselected from the following substituent group b; R⁸ represents a C₆₋₁₄aromatic hydrocarbon cyclic group or a 5- to 14-membered aromaticheterocyclic group which may have a substituent group, respectively; andring A represents a nitrogen-containing 6-membered ring which may besubstituted with 1 to 4 groups selected from the following substituentgroup b. <substituent group b> a group consisting of hydrogen atom, ahalogen atom, hydroxyl group, nitro group, cyano group, an optionallysubstituted C₁₋₆ alkyl group, an optionally substituted C₁₋₆ alkylgroup, an optionally substituted C₂₋₆ alkenyl group, an optionallysubstituted C₂₋₆ alkynyl group, an optionally substituted C₁₋₆ alkoxygroup, an optionally substituted C₂₋₆ alkenyloxy group, an optionallysubstituted C₂₋₆ alkynyloxy group, an optionally substituted C₁₋₆alkylthio group, an optionally substituted C₂₋₆ alkenylthio group, anoptionally substituted C₂₋₆ alkynylthio group, a C₂₋₇ fatty acyl group,an optionally substituted carbamoyl group, an arylacyl group, aheteroaryl acyl group, an optionally substituted amino group, anoptionally substituted C₁₋₆ alkylsulfonyl group, an optionallysubstituted C₂₋₆ alkenylsulfonyl group, an optionally substituted C₂₋₆alkynylsulfonyl group, an optionally substituted C₁₋₆ alkylsulfinylgroup, an optionally substituted C₂₋₆ alkenylsulfinyl group, anoptionally substituted C₂₋₆ alkynylsulfinyl group, formyl group, anoptionally substituted C₃₋₈ cycloalkyl group, an optionally substitutedC₃₋₈ cycloalkenyl group, an optionally substituted 5- to 14-memberednon-aromatic heterocyclic group, an optionally substituted C₆₋₁₄aromatic hydrocarbon cyclic group and an optionally substituted 5- to14-membered aromatic heterocyclic group) or a salt thereof; (15) thecompound according to the above-mentioned (14) or a salt thereof, inwhich R¹ is cyano group; (16) the compound according to theabove-mentioned (14) or a salt thereof, in which R¹is carboxyl group;(17) the compound according to the above-mentioned (14) or a saltthereof, in which R¹ is a carbamoyl group represented by the formula:

[0025] in which R⁵ and R⁶ have the same meanings as defined above; (18)the compound according to the above-mentioned (14) or a salt thereof, inwhich R² is a hydrogen atom; (19) the compound according to theabove-mentioned (14) or a salt thereof, in which R⁷ and the substituentgroups other than R⁷ in the ring A are selected from the above-mentionedsubstituent group a; (20) the compound according to the above-mentioned(14) or a salt thereof, in which R⁷ is hydrogen atom, an optionallysubstituted C₁₋₆ alkyl group, an optionally substituted C₂₋₆ alkenylgroup or an optionally substituted C₁₋₆ alkoxy group; (21) the compoundaccording to the above-mentioned (14) or a salt thereof, in which R⁸ isa phenyl group, pyridyl group, furyl group or a thienyl group, each ofwhich may have a substituent group; (22) the compound according to theabove-mentioned (14) or a salt thereof, in which R⁸ is a phenyl group,pyridyl group, furyl group or a thienyl group, each of which may besubstituted with a halogen atom; (23) the compound according to theabove-mentioned (1), in which the compound is any one selected from2-amino-6-(2-furyl)-5-(4-pyridyl)-3-pyridinecarbonitrile,2-amino-6-(3-fluorophenyl)-5-(4-pyridyl)-3-pyridinecarbonitrile,2-amino-6-(2-furyl)-5-(4-methoxy-3-pyridyl)-3-pyridinecarbonitrile,2-amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile,2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinonitrile,2-amino-6-(2-furyl)-5-(1-methyl-6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile,2-amino-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrileand2-amino-6-(3-fluorophenyl)-5-(1-methyl-6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile,or a salt thereof; (24) a pharmaceutical composition comprising acompound represented by the formula:

[0026] (wherein R¹ represents cyano group, carboxyl group or anoptionally substituted carbamoyl group; R² represents hydrogen atom,hydroxyl group, an optionally substituted C₁₋₆ alkoxy group, anoptionally substituted C₆₋₁₄ aromatic hydrocarbon cyclic group or anoptionally substituted 5- to 14-membered aromatic heterocyclic group;and R³ and R⁴ are the same as or different from each other and eachrepresents a C₃₋₈ cycloalkyl group, a C₃₋₈ cycloalkenyl group, a C₆₋₁₄aromatic hydrocarbon cyclic group, a 5- to 14-membered non-aromaticheterocyclic group or a 5- to 14-membered aromatic heterocyclic groupwhich may have a substituent group, respectively, provided that thecases where (1) R¹ is cyano group, R² is 4-bromo-2-thienyl group, R³ is3,4-dimethoxyphenyl group and R⁴ is 2-thienyl group, (2) R¹ is cyanogroup, R² is hydrogen atom and each of R³ and R⁴ is phenyl group, (3) R¹is cyano group, R² is 4-chloro-phenyl group, R³ is phenyl group and R⁴is 4-(3,4-dichlorophenyl)-1-oxo-2(1H)-phthalazinyl group, (4) R¹ iscyano group, R² is hydrogen atom, R³ is 4-pyridyl group and R⁴ is1-piperazinyl group, (5) R¹ is cyano group, R² is hydrogen atom, R³ is4-pyridyl group and R⁴ is 1-pyridyl group, (6) R¹ is cyano group, R² ishydrogen atom, R³ is 4-pyridyl group and R⁴ is4-diphenylmethyl-1-piperazinyl group, (7) R¹ is cyano group, R² ishydrogen atom, R³ is 4-pyridyl group and R⁴ is 4-morpholinyl group, (8)R¹ is cyano group, R² is 4-methylphenyl group and each of R³ and R⁴ isphenyl group, and (9) R¹ is cyano group and each of R², R³ and R⁴ isphenyl group are excluded) or a salt thereof; (25) the compositionaccording to the above-mentioned (24), which is an agent for treating orpreventing a disease to which an adenosine receptor relates; (26) thecomposition according to the above-mentioned (24), which is an agent fortreating or preventing a disease to which an adenosine A₂ receptorrelates; (27) the composition according to the above-mentioned (24),which is an agent for treating or preventing a disease to which anadenosine A_(2B) receptor relates; (28) the composition according to theabove-mentioned (24), which is an adenosine receptor antagonist; (29)the composition according to claim 24, which is an adenosine A₂ receptorantagonist; (30) the composition according to the above-mentioned (24),which is an adenosine A_(2B) receptor antagonist; (31) the compositionaccording to the above-mentioned (24), which is used for promotingdefecation; (32) the composition according to the above-mentioned (24),which is an agent for treating, preventing or improving constipation;(33) the composition according to the above-mentioned (24), in which theconstipation is functional constipation; (34) the composition accordingto the above-mentioned (24), which is an agent for treating irritablebowel syndrome, constipation accompanying irritable bowel syndrome,organic constipation, constipation accompanying enteroparalytic ileus,constipation accompanying congenital digestive tract dysfunction orconstipation accompanying ileus; (35) the composition according to theabove-mentioned (24), which is used for evacuating intestinal tracts atthe time of examination of digestive tracts or before and after anoperation; (36) the composition according to the above-mentioned (24),which is an agent for treating or preventing diabetes, diabeticcomplications, diabetic retinopathy, obesity or asthma; (37) thecomposition according to the above-mentioned (24), which is ahypoglycemic agent, an improving agent for impaired glucose toleranceand a potentiating agent for insulin sensitivity; (38) the compositionaccording to the above-mentioned (24), which is a hypotensive agent, adiuretic, a therapeutic agent for osteoporosis, an anti-Parkinson'sdisease agent, an anti-Alzheimer's disease agent, a therapeutic agentfor inflammatory intestinal diseases or a therapeutic agent for Crohn'sdisease, etc.

[0027] That is, the present invention is a pharmaceutical compositioncomprising the above-mentioned 2-aminopyridine compound or apharmacologically acceptable salt thereof and a pharmaceuticallyacceptable carrier, use of the above-mentioned compound or apharmacologically acceptable salt thereof for producing an agent fortreating or preventing a disease to which an adenosine receptor relates,and a method of treating or preventing a disease to which an adenosinereceptor relates, by administering a pharmacologically effective dose ofthe above-mentioned compound or a pharmacologically acceptable saltthereof to a patient.

DETAILED DESCRIPTION OF THE INVENTION

[0028] Hereinafter, the meanings of symbols, terms etc. used in thepresent specification are described, and the present invention isdescribed in detail.

[0029] The “antagonist” in this specification refers to an agent havingaffinity for adenosine receptors, particularly adenosine A₂ receptor(most preferably A_(2B) receptor) and inactivating the receptor.

[0030] In this specification, the “disease to which an adenosinereceptor relates” means a disease to which an adenosine A₁ receptor,A_(2a) receptor, A_(2b) receptor or A₃ receptor relates. For example,various kinds of constipation, irritable bowel syndrome, constipationaccompanying irritable bowel syndrome, organic constipation,constipation accompanying intestinal paralytic ileus, constipationaccompanying congenital digestive tract dysfunction, constipationaccompanying ileus, diabetes, diabetic complications, diabeticretinopathy, obesity or asthma, or a disease against which ahypoglycemic agent, an improving agent for impaired glucose tolerance, apotentiating agent for insulin sensitivity, a hypotensive agent, adiuretic, a therapeutic agent for osteoporosis, an anti-Parkinson'sdisease agent, an anti-Alzheimer's disease agent, a therapeutic agentfor inflammatory intestinal diseases or a therapeutic agent for Crohn'sdisease is efficacious.

[0031] The term “and/or” used in this specification refers to both of“and” and “or”.

[0032] The structural formulae of the compound in this specificationmay, for convenience' sake, indicate a certain isomer, but the presentinvention encompasses all possible isomers which can occur in thestructures of the compound, for example, geometric isomer, opticalisomer based on asymmetrical carbon, rotational isomer, stereoisomer andtautomer, as well as a mixture of such isomers, so the compound of theinvention may be any isomers or a mixture thereof without limitation tothe formulae shown for convenience' sake. Accordingly, the compound ofthe present invention can have an intramolecular asymmetrical carbon tooccur as optically active isomers or racemic modifications, and any ofsuch compounds are included in the present invention without limitation.Further, crystal polymorphism may present also without limitation, andit may be in a single crystal form or a mixed crystal form. The compound(I) according to the present invention or a salt thereof may beanhydrides or hydrates, any of which fall under the claims in thepresent specification. Metabolites formed by decomposition of theCompound (I) according to the present invention in vivo, as well asprodrugs of the compound (I) according to the present invention or asalt thereof also fall under the claims in the present specification.

[0033] As the “halogen atom” used in the present specification, forexample, atoms such as fluorine atom, chlorine atom, bromine atom,iodine atom etc. may be proposed, and fluorine atom, chlorine atom andbromine atom are preferred.

[0034] The “C₁₋₆ alkyl group” used in this specification refers to analkyl group containing 1 to 6 carbon groups, and examples thereofinclude linear or branched alkyl groups such as methyl group, ethylgroup, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group,sec-butyl group, tert-butyl group, n-pentyl group, 1,1-dimethylpropylgroup, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropylgroup, 2-ethylpropyl group, n-hexyl group, 1-methyl-2-ethylpropyl group,1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group,1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group,1,1,-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutylgroup, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutylgroup, 2-methylpentyl group or 3-methylpentyl group may be proposed.

[0035] The “C₂₋₆ alkenyl group” used in this specification refers to analkenyl group containing 2 to 6 carbon atoms. As the preferable examplesthereof, for example, vinyl group, allyl group, 1-propenyl group,2-propenyl group, isopropenyl group, 2-methyl-1-propenyl group,3-methyl-1-propenyl group, 2-methyl-2-propenyl group,3-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenylgroup, 1-pentenyl group, 1-hexenyl group, 1,3-hexanedienyl group,1,6-hexanedienyl group etc. may be proposed.

[0036] The “C₂₋₆ alkynyl group” used in this specification refers to analkynyl group containing 2 to 6 carbon atoms. As the preferable examplesthereof, for example, ethynyl group, 1-propynyl group, 2-propynyl group,1-butynyl group, 2-butynyl group, 3-butynyl group, 3-methyl-1-propynylgroup, 1-ethynyl-2-propynyl group, 2-methyl-3-propynyl group, 1-pentynylgroup, 1-hexynyl group, 1,3-hexanediynyl group, 1,6-hexanediynyl groupetc. may be proposed.

[0037] The “C₁₋₆ alkoxy group” used in this specification refers to analkoxy group containing 1 to 6 carbon groups, for example, methoxygroup, ethoxy group, n-propoxy group, iso-propoxy group, sec-propoxygroup, n-butoxy group, iso-butoxy group, sec-butoxy group, tert-butoxygroup, n-pentyloxy group, iso-pentyloxy group, sec-pentyloxy group,n-hexoxy group, iso-hexoxy group, 1,1-dimethylpropyloxy group,1,2-dimethylpropoxy group, 2,2-dimethylpropyloxy group, 2-ethylpropoxygroup, 1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group,1,1,2-trimethylpropoxy group, 1,1,2-trimethylpropoxy group,1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2-dimethylbutoxygroup, 2,3-dimethylbutyloxy group, 1,3-dimethylbutyloxy group,2-ethylbutoxy group, 1,3-dimethylbutoxy group, 2-methylpentoxy group,3-methylpentoxy group, hexyloxy group etc.

[0038] The “C₂₋₆ alkenyloxy group” used in this specification refers toan alkenyloxy group containing 2 to 6 carbon atoms. As the preferablegroup, for example, vinyloxy group, allyloxy group, 1-propenyloxy group,2-propenyloxy group, isopropenyloxy group, 2-methyl-1-propenyloxy group,3-methyl-1-propenyloxy group, 2-methyl-2-propenyloxy group,3-methyl-2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy group,3-butenyloxy group, 1-pentenyloxy group, 1-hexenyloxy group,1,3-hexanedienyloxy group, 1,6-hexanedienyloxy group etc. may beproposed.

[0039] The “C₂₋₆ alkynyloxy group” used in this specification refers toan alkynyloxy group containing 2 to 6 carbon atoms. Preferably, forexample, ethynyloxy group, 1-propynyloxy group, 2-propynyloxy group,1-butynyloxy group, 2-butynyloxy group, 3-butynyloxy group,3-methyl-1-propynyloxy group, 1-ethynyl-2-propynyloxy group,2-methyl-3-propynyloxy group, 1-pentynyloxy group, 1-hexynyloxy group,1,3-hexanediynyloxy group, 1,6-hexanediynyloxy group etc. may beproposed.

[0040] The “C₁₋₆ alkylthio group” used in this specification refers toan alkoxy group containing 1 to 6 carbon groups. For example, methylthiogroup, ethylthio group, n-propylthio group, iso-propylthio group,sec-propylthio group, n-butylthio group, iso-butylthio group,sec-butylthio group, tert-butylthio group, n-pentylthio group,iso-pentylthio group, sec-pentylthio group, n-hexylthio group,iso-hexylthio group, 1,1-dimethylpropylthio group,1,2-dimethylpropylthio group, 2,2-dimethylpropylthio group,2-ethylpropylthio group, 1-methyl-2-ethylpropylthio group,1-ethyl-2-methylpropylthio group, 1,1,2-trimethylpropylthio group,1,1,2-trimethylpropylthio group, 1,1,-dimethylbutylthio group,1,2-dimethylbutylthio group, 2,2-dimethylbutylthio group,2,3-dimethylbutylthio group, 1,3-dimethylbutylthio group,2-ethylbutylthio group, 1,3-dimethylbutylthio group, 2-methylpentylthiogroup, 3-methylpentylthio group etc. may be proposed. The “C₂₋₆alkenylthio group” used in this specification refers to an alkenylthiogroup containing 2 to 6 carbon atoms. The preferable examples thereofinclude vinylthio group, allylthio group, 1-propenylthio group,2-propenylthio group, isopropenylthio group, 2-methyl-1-propenylthiogroup, 3-methyl-1-propenylthio group, 2-methyl-2-propenylthio group,3-methyl-2-propenylthio group, 1-butenylthio group, 2-butenylthio group,3-butenylthio group, 1-pentenylthio group, 1-hexenylthio group,1,3-hexanedienylthio group, 1,6-hexanedienylthio group, etc. The “C₂₋₆alkynylthio group” used in this specification refers to an alkynylthiogroup containing 2 to 6 carbon atoms. The preferable examples thereofinclude ethynylthio group, 1-propynylthio group, 2-propynylthio group,1-butynylthio group, 2-butynylthio group, 3-butynylthio group,3-methyl-1-propynylthio group, 1-ethynyl-2-propynylthio group,2-methyl-3-propynylthio group, 1-pentynylthio group, 1-hexynylthiogroup, 1,3-hexanediynylthio group, 1,6-hexanediynylthio group, etc.

[0041] The “C₃₋₈ cycloalkyl group” used in this specification refers toa cycloalkyl group containing 3 to 8 carbon atoms, and examples thereofinclude cyclopropyl group, cyclobutyl group, cyclopentyl group,cyclohexyl group, cycloheptyl group, cyclooctyl group etc.

[0042] The “C₃₋₈ cycloalkenyl group” used in this specification refersto a C₃₋₈ cycloalkenyl group containing 3 to 8 carbon atoms. Forexample, cyclopropen-1-yl, cyclopropen-3-yl, cyclobuten-1-yl,cyclobuten-3-yl, 1,3-cyclobutadien-1-yl, cyclopenten-1-yl,cyclopenten-3-yl, cyclopenten-4-yl, 1,3-cyclopentadien-1-yl,1,3-cyclopentadien-2-yl, 1,3-cyclopentadien-5-yl, cyclohexen-1-yl,cyclohexen-3-yl, cyclohexen-4-yl, 1,3-cyclohexadien-1-yl,1,3-cyclohexadien-2-yl, 1,3-cyclohexadien-5-yl, 1,4-cyclohexadien-3-yl,1,4-cyclohexadien-1-yl, cyclohepten-1-yl, cyclohepten-3-yl,cyclohepten-4-yl, cyclohepten-5-yl, 1,3-cyclohepten-2-yl,1,3-cyclohepten-1-yl, 1,3-cycloheptadien-5-yl, 1,3-cycloheptadien-6-yl,1,4-cycloheptadien-3-yl, 1,4-cycloheptadien-2-yl,1,4-cycloheptadien-1-yl,1,4-cycloheptadien-6-yl,1,3,5-cycloheptatrien-3-yl, 1,3,5-cycloheptatrien-2-yl,1,3,5-cycloheptatrien-1-yl, 1,3,5-cycloheptatrien-7-yl, cycloocten-1-yl,cycloocten-3-yl, cycloocten-4-yl, cycloocten-5-yl,1,3-cyclooctadien-2-yl, 1,3-cyclooctadien-1-yl, 1,3-cyclooctadien-5-yl,1,3-cyclooctadien-6-yl, 1,4-cyclooctadien-3-yl, 1,4-cyclooctadien-2-yl,1,4-cyclooctadien-1-yl, 1,4-cyclooctadien-6-yl, 1,4-cyclooctadien-7-yl,1,5-cyclooctadien-3-yl, 1,5-cyclooctadien-2-yl,1,3,5-cyclooctatrien-3-yl, 1,3,5-cyclooctatrien-2-yl,1,3,5-cyclooctatrien-1-yl, 1,3,5-cyclooctatrien-7-yl,1,3,6-cyclooctatrien-2-yl, 1,3,6-cyclooctatrien-1-yl,1,3,6-cyclooctatrien-5-yl, 1,3,6-cyclooctatrien-6-yl group, etc. may beproposed.

[0043] The “5- to 14-membered non-aromatic heterocyclic group” used inthis specification refers to a monocyclic, bicyclic or tricyclic, 5- to14-membered non-aromatic heterocyclic group containing at least oneheteroatom selected from nitrogen atom, sulfur atom and oxygen atom.Specific examples of the group include pyrrolidinyl group, pyrrolylgroup, piperidinyl group, piperazinyl group, imidazolyl group,pyrazolidyl group, imidazolidyl group, morpholyl group, tertrahydrofurylgroup, tetrahydropyranyl group, pyrrolinyl group, dihydrofuryl group,dihydropyranyl group, imidazolinyl group, oxazolinyl group, etc.Further, the non-aromatic heterocyclic group also includes a groupderived from a pyridone ring or a non-aromatic fused ring (for example,a group derived from a phthalimide ring, succinimide ring, etc.).

[0044] The “C₆₋₁₄ aromatic hydrocarbon cyclic group” and “aryl” used inthis specification refer to an aromatic hydrocarbon cyclic groupcontaining 6 to 14 carbon atoms, and include a monocyclic group and acondensed ring such as bicyclic group, tricyclic group etc. Specificexamples of this group include phenyl group, indenyl group, 1-naphthylgroup, 2-naphthyl group, azulenyl group, heptalenyl group, biphenylgroup, indacenyl group, acenaphthyl group, fluorenyl group, phenalenylgroup, phenanthrenyl group, anthracenyl group, cyclopentacyclooctenylgroup, benzocyclooctenyl group, etc. may be proposed.

[0045] In this specification, the “5- to 14-membered aromaticheterocyclic group” and “heteroaryl” refer to a monocyclic, bicyclic ortricyclic, 5- to 14-membered aromatic heterocyclic group containing atleast one heteroatom selected from nitrogen atom, sulfur atom and oxygenatom. Specific examples of the group include, for example, 1)nitrogen-containing aromatic heterocyclic groups such as pyrrolyl group,pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group,triazolyl group, tetrazolyl group, benzotriazolyl group, pyrazolylgroup, imidazolyl group, benzimidazolyl group, indolyl group, isoindolylgroup, indolizinyl group, purinyl group, indazolyl group, quinolylgroup, isoquinolyl group, quinolizyl group, phthalazyl group,naphthyridinyl group, quinoxalyl group, quinazolinyl group, cinnolinylgroup, pteridinyl group, imidazotriazinyl group, pyrazinopyridazinylgroup, acridinyl group, phenanthridinyl group, carbazolyl group,carbazolinyl group, pyrimidinyl group, phenanthrolinyl group, phenacynylgroup, imidazopyridinyl group, imidazopyrimidinyl group,pyrazolopyridinyl group, pyrazolopyridinyl group, etc.; 2)sulfur-containing aromatic heterocyclic groups such as thienyl group,benzothienyl group, etc.; 3) oxygen-containing aromatic heterocyclicgroups such as furyl group, pyranyl group, cyclopentapyranyl group,benzofuryl group, isobenzofuryl group, etc.; and 4) aromaticheterocyclic group containing two or more heteroatoms, such as thiazolylgroup, isothiazolyl group, benzothiazolyl group, benzthiadiazolyl group,phenothiazinyl group, isoxazolyl group, furazanyl group, phenoxazinylgroup, oxazolyl group, isoxazoyl group, benzoxazolyl group, oxadiazolylgroup, pyrazolooxazolyl group, imidazothiazolyl group, thienofuranylgroup, furopyrrolyl group, pyridoxazinyl group, etc.

[0046] The “C₂₋₇ fatty acyl group” used in this specification refers toan atomic group derived by removing an OH group from a carboxyl group ofa C₂₋₇ fatty carboxylic acid. As the preferable group thereof, forexample, acetyl group, propionyl group, butyroyl group, etc. may beproposed.

[0047] The “arylacyl group” used in this specification refers to acarbonyl group substituted with a C₆₋₁₄ aromatic hydrocarbon cyclicgroup, and the “heteroarylacyl group” refers to a carbonyl groupsubstituted with a 5- to 14-membered aromatic heterocyclic group. The“C₆₋₁₄ aromatic hydrocarbon cyclic group” and “5- to 14-memberedaromatic heterocyclic group” have the same meaning as defined above.

[0048] Preferable examples of the “C₁₋₆ alkylsulfonyl group”, “C₂₋₆alkenylsulfonyl group” and “C₂₋₆ alkynylsulfonyl group” used in thisspecification include methylsulfonyl group, ethylsulfonyl group,n-propylsulfonyl group, iso-propylsulfonyl group, n-butylsulfonyl group,tert-butylsulfonyl group, vinylsulfonyl group, allylsulfonyl group,iso-propenylsulfonyl group, iso-pentenylsulfonyl group, ethynylsulfonylgroup etc. Preferable examples of the “C₁₋₆ alkylsulfinyl group”, “C₂₋₆alkenylsulfinyl group” and “C₂₋₆ alkynylsulfinyl group” used in thisspecification include methylsulfinyl group, ethylsulfinyl group,n-propylsulfinyl group, iso-propylsulfinyl group, n-butylsulfinyl group,tert-butylsulfinyl group, vinylsulfinyl group, allylsulfinyl group,iso-propenylsulfinyl group, iso-pentenylsulfinyl group, ethynylsulfinylgroup, etc.

[0049] As the “substituent group” in the “optionally substituted aminogroup” used in this specification, for example, one or two groupsselected from a C₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynylgroup, C₁₋₆ alkylsulfonyl group, C₂₋₆ alkenylsulfonyl group, C₂₋₆alkynylsulfonyl group, C₁₋₆ alkylcarbonyl group, C₂₋₆ alkenylcarbonylgroup and C₂₋₆ alkynylcarbonyl group, each of which may have asubstituent group may be proposed, and the substituent groups may bebound together to form a 3- to 8-membered nitrogen-containing ring.Preferable examples of the “substituent group” of the above-mentionedC₁₋₆ alkyl group, C₂₋₆ alkenyl group, C₂₋₆ alkynyl group, C₁₋₆alkylsulfonyl group, C₂₋₆ alkenylsulfonyl group, C₂₋₆ alkynylsulfonylgroup, C₁₋₆ alkylcarbonyl group, C₂₋₆ alkenylcarbonyl group and C₂₋₆alkynylcarbonyl group include hydroxyl group, a halogen atom, nitrilegroup, a C₁₋₆ alkoxy group, a C₁₋₆ alkylthio group, etc. Specifically,as the particularly preferable examples of the above-mentioned “aminogroup which may have a substituent group”, methylamino group, ethylaminogroup, n-propylamino group, iso-propylamino group, n-butylamino group,iso-butylamino group, tert-butylamino group, n-pentylamino group,iso-pentylamino group, neopentylamino group, n-hexylamino group,1-methylpropylamino group, 1,2-dimethylpropylamino group,2-ethylpropylamino group, 1-methyl-2-ethylpropylamino group,1-ethyl-2-methylpropylamino group, 1,1,2-trimethylpropylamino group,1-methylbutylamino group, 2-methylbutylamino group,1,1-dimethylbutylamino group, 2,2-dimethylbutylamino group,2-ethylbutylamino group, 1,3-dimethylbutylamino group,2-methylpentylamino group, 3-methylpentylamino group, N,N-dimethylaminogroup, N,N-diethylamino group, N,N-di(n-propyl)amino group,N,N-di(iso-propyl)amino group, N,N-di(n-butyl)amino group,N,N-di(iso-butyl)amino group, N,N-di(tert-butyl)amino group,N,N-di(n-pentyl)amino group, N,N-di(iso-pentyl)amino group,N,N-di(neopentyl)amino group, N,N-di(n-hexyl)amino group,N,N-di(l-methylpropyl)amino group, N,N-di(1,2-dimethylpropyl)aminogroup, N-methyl-N-ethylamino group, N-ethyl-N-(n-propyl)amino group,N-methyl-N-(i-propyl)amino group, vinylamino group, allylamino group,(1-propenyl)amino group, isopropenylamino group, (1-buten-1-yl)aminogroup, (1-buten-2-yl)amino group, (1-buten-3-yl)amino group,(2-buten-1-yl)amino group, (2-buten-2-yl)amino group, N,N-divinylaminogroup, N,N-diallylamino group, N,N-di(1-propenyl)amino group,N,N-isopropenylamino group, N-vinyl-N-allylamino group, ethynylaminogroup, 1-propynylamino group, 2-propynylamino group, butynylamino group,pentynylamino group, hexynylamino group, N,N-diethynylamino group,N,N-(1-propynyl)amino group, N,N-(2-propynyl)amino group,N,N-dibutynylamino group, N,N-dipentynylamino group, N,N-dihexynylaminogroup, hydroxymethylamino group, 1-hydroxyethylamino group,2-hydroxyethylamino group, 3-hydroxy-n-propyl group, methylsulfonylaminogroup, ethylsulfonylamino group, n-propylsulfonylamino group,iso-propylsulfonylamino group, n-butylsulfonylamino group,tert-butylsulfonylamino group, vinylsulfonylamino group,allylsulfonylamino group, iso-propenylsulfonylamino group,iso-pentenylsulfonylamino group, ethynylsulfonylamino group,methylcarbonylamino group, ethylcarbonylamino group,n-propylcarbonylamino group, iso-propylcarbonylamino group,n-butylcarbonylamino group, tert-butylcarbonylamino group,vinylcarbonylamino group, allylcarbonylamino group,iso-propenylcarbonylamino group, iso-pentenylcarbonylamino group,ethynylcarbonylamino group, etc.

[0050] As the “substituent group” in the “which may have a substituentgroup” used in this specification, a halogen atom (for example, fluorineatom, chlorine atom, bromine atom, iodine atom etc.), hydroxyl group,nitro group, cyano group, a C₁₋₆ alkyl group (for example, methyl group,ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butylgroup, sec-butyl group, tert-butyl group, n-pentyl group,1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropylgroup, 1-ethylpropyl group, 2-ethylpropyl group, n-hexyl group,1-methyl-2-ethylpropyl group etc.), a C₂₋₆ alkenyl group (for example,vinyl group, allyl group, 1-propenyl group, 2-propenyl group,isopropenyl group, 2-methyl-1-propenyl group, 3-methyl-1-propenyl group,2-methyl-2-propenyl group, 3-methyl-2-propenyl group, 1-butenyl group,2-butenyl group, 3-butenyl group, 1-pentenyl group, 1-hexenyl group,1,3-hexanedienyl group, 1,6-hexanedienyl group, etc.), a C₂₋₆ alkynylgroup (for example, ethynyl group, 1-propynyl group, 2-propynyl group,1-butynyl group, 2-butynyl group, 3-butynyl group, 3-methyl-1-propynylgroup, 1-ethynyl-2-propynyl group, 2-methyl-3-propynyl group, 1-pentynylgroup, 1-hexynyl group, 1,3-hexanediynyl group, 1,6-hexanediynyl group,etc.), a C₁₋₆ alkoxy group (for example, methoxy group, ethoxy group,n-propoxy group, iso-propoxy group, sec-propoxy group, n-butoxy group,iso-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxygroup, iso-pentyloxy group, sec-pentyloxy group, n-hexoxy group, etc.),a C₂₋₆ alkenyloxy group (for example, vinyloxy group, allyloxy group,1-propenyloxy group, 2-propenyloxy group, isopropenyloxy group, etc.), aC₂₋₆ alkynyloxy group (for example, ethynyloxy group, 1-propynyloxygroup, 2-propynyloxy group, etc.), a C₁₋₆ alkylthio group (for example,methylthio group, ethylthio group, n-propylthio group, iso-propylthiogroup, sec-propylthio group, n-butylthio group, iso-butylthio group,sec-butylthio group, tert-butylthio group, etc.), a C₂₋₆ alkenylthiogroup (for example, vinylthio group, allylthio group, 1-propenylthiogroup, 2-propenylthio group, etc.), a C₂₋₆ alkynylthio group (forexample, ethynylthio group, 1-propynylthio group, 2-propynylthio group,etc.), a C₂₋₇ fatty acyl group (for example, acetyl group, propionylgroup, butyroyl group, etc.), carbamoyl group, arylacyl group,heteroarylacyl group, amino group, a C₁₋₆ alkylsulfonyl group, a C₂₋₆alkenylsulfonyl group, a C₂₋₆ alkynylsulfonyl group, a C₁₋₆alkylsulfinyl group, C₂₋₆ alkenylsulfinyl group, a C₂₋₆ alkynylsulfinylgroup (for example, methylsulfonyl group, ethylsulfonyl group,n-propylsulfonyl group, iso-propylsulfonyl group, n-butylsulfonyl group,tert-butylsulfonyl group, vinylsulfonyl group, allylsulfonyl group,iso-propenylsulfonyl group, iso-pentenylsulfonyl group, ethynylsulfonylgroup, methylsulfinyl group, ethylsulfinyl group, n-propylsulfinylgroup, iso-propylsulfinyl group, n-butylsulfinyl group,tert-butylsulfinyl group, vinylsulfinyl group, allylsulfinyl group,iso-propenylsulfinyl group, iso-pentenylsulfinyl group, ethynylsulfinylgroup, etc.), formyl group, a C₃₋₈ cycloalkyl group (for example,cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexylgroup, cycloheptyl group, cyclooctyl group etc.), a C₃₋₈ cycloalkenylgroup (for example, cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl group, etc.), a 5- to 14-membered non-aromatic heterocyclicgroup (for example, pyrrolidinyl group, pyrrolyl group, piperidinylgroup, piperazinyl group, imidazolyl group, pyrazolidyl group,imidazolidyl group, morpholyl group, tertrahydrofuryl group,tetrahydropyranyl group, pyrrolinyl group, dihydrofuryl group,dihydropyranyl group, imidazolinyl group, oxazolinyl group, a groupderived from a pyridone ring, a group derived from a phthalimide ring orsuccinimide ring, etc.), a C₆₋₁₄ aromatic hydrocarbon cyclic group (forexample, phenyl group, indenyl group, 1-naphthyl group, 2-naphthylgroup, biphenyl group, indacenyl group etc.), a 5- to 14-memberedaromatic heterocyclic ring (for example, pyrrolyl group, pyridyl group,pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl group,tetrazolyl group, benzotriazolyl group, pyrazolyl group, imidazolylgroup, benzimidazolyl group, indolyl group, iso-indolyl group,indolizinyl group, purinyl group, indazolyl group, quinolyl group,iso-quinolyl group, quinolizyl group, phthalazyl group, naphthylidinylgroup, quinoxalyl group, quinazolinyl group, cynnolinyl group,pteridinyl group, imidazotriazinyl group, pyrazinopyridazinyl group,acridinyl group, phenanthridinyl group, carbazolyl group, carbazolinylgroup, perimidinyl group, phenanthrolinyl group, phenacinyl group,imidazopyridinyl group, imidazopyrimidinyl group, pyrazolopyridinylgroup, pyrazolopyridinyl group, thienyl group, benzothienyl group, furylgroup, pyranyl group, cyclopentapyranyl group, benzofuryl group,iso-benzofuryl group, thiazolyl group, iso-thiazolyl group,benzothiazolyl group, benzthiadiazolyl group, phenothiazinyl group,isoxazolyl group, furazanyl group, phenoxazinyl group, oxazolyl group,isoxazoyl group, benzoxazolyl group, oxadiazolyl group, pyrazoloxazolylgroup, imidazothiazolyl group, thienofuranyl group, furopyrrolyl group,pyridoxadinyl group etc.), and these substituent groups may further havesubstituent groups.

[0051] In the formula (I) above, R¹ represents cyano group, carboxylgroup or a carbamoyl group which may have a substituent group, and themost preferable group is not particularly limited. As the preferableexample of the “substituent group” in the “carbamoyl group which mayhave a substituent group”, a group selected from a C₁₋₆ alkyl groupwhich may have a substituent group, a C₂₋₆ alkenyl group which may havea substituent group, a C₂₋₆ alkynyl group which may have a substituentgroup, a C₃₋₈ cycloalkyl group which may have a substituent group, aC₃₋₈ cycloalkenyl group which may have a substituent group, a C₆₋₁₄aromatic hydrocarbon cyclic group which may have a substituent group, a5- to 14-membered aromatic heterocyclic group which may have asubstituent group etc. may be proposed. The nitrogen atom in thecarbamoyl group may be substituted with one or two groups selected fromthe substituent groups described above. Further, the above-mentionedsubstituent groups may be bound together to form a 3- to 14-memberednitrogen-containing ring (for example, pyrrolidyl group, pyrrolinylgroup, piperidyl group, piperazinyl group, imidazolyl group, pyrazolidylgroup, imidazolidyl group, morpholinyl group, tetrahydropyranyl group,aziridinyl group, oxiranyl group, oxathiolanyl group, phthalimidoylgroup, succinimidyl group, pyrrolyl group, pyridyl group, pyridazinylgroup, pyrimidinyl group, pyrazinyl group, pyrazolyl group, etc.), andthe nitrogen-containing rings may further have substituent groups.

[0052] Preferable groups of R² in the formula (I) above are notparticularly limited, but more preferable groups include hydrogen atom,a C₁₋₆ alkoxy group, phenyl, naphthyl, pyridyl, pyridazyl, pyrimidyl,pyrazyl, thienyl, furyl and imidazolyl groups, each of which may have asubstituent group, and further preferably hydrogen atom.

[0053] In the formula (I) above, R³ and R⁴ are independent of each otherand each represents a C₃₋₈ cycloalkyl group, a C₃₋₈ cycloalkenyl group,a C₆₋₁₄ aromatic hydrocarbon cyclic group, a 5- to 14-memberednon-aromatic heterocyclic group or a 5- to 14-membered aromaticheterocyclic group, each of which may have a substituent group, andpreferable groups include a C₆₋₁₄ aromatic hydrocarbon cyclic group (forexample, phenyl group, naphthyl group etc.), a 5- to 14-memberednon-aromatic heterocyclic group (for example, pyrrolidinyl group,pyrrolinyl group, piperidinyl group, piperazinyl group, imidazolinylgroup, pyrazolidinyl group, imidazolidinyl, morpholinyl group,tetrahydropyranyl group, aziridinyl group, oxiranyl group, oxathiolanylgroup, a 6-oxo-1,6-dihydropyridyl group whose nitrogen atom may besubstituted etc.) or a 5- to 14-membered aromatic heterocyclic group(for example, pyrrolyl group, pyridyl group, pyridazinyl group,pyrimidinyl group, pyrazinyl group, pyrazolyl group, imidazolyl group,indolyl group, isoindolyl group, indolizinyl group, quinolinyl group,isoquinolinyl group, quinolizinyl group, phthalazinyl group,naphthyridyl group, quinoxalyl group, quinazolyl group, imidazotriazinylgroup, pyrazinopyridazinyl group, thienyl group, benzothienyl group,furyl group, pyranyl group, cyclopentapyranyl group, benzofuryl group,isobenzofuryl group, thiazolyl group, isothiazolyl group, benzthiazolylgroup, benzthiadiazolyl group, phenothiazyl group, isoxazolyl group,pyrazoloxazolyl group, imidazothiazolyl group, thienofuryl group,furopyrrolyl group, pyridoxazinyl group etc.), and these substituentgroups may have substituent groups. As the more preferable examples ofR³ and R⁴, for example, groups represented by the formulae:

[0054] which may be substituted, respectively. When the above-mentioned6-oxo-1,6-dihydropyridyl group has a substituent group, the case wherethe substituent group is bound to the nitrogen atom is also included.

[0055] As the “substituent” in the “C₃₋₈ cycloalkyl group which may havea substituent group”, “C₃₋₈ cycloalkenyl group which may have asubstituent group”, “C₆₋₁₄ aromatic hydrocarbon cyclic group which mayhave a substituent group”, “5- to 14-membered non-aromatic heterocyclicgroup which may have a substituent group” and “5- to 14-memberedaromatic heterocyclic group which may have a substituent group”represented by R³ and R⁴, (1) one or more groups selected from hydroxylgroup, a halogen atom, cyano group, nitro group, a C₁₋₆ alkyl groupwhich may have a substituent group, a C₂₋₆ alkenyl group which may havea substituent group, a C₂₋₆ alkynyl group which may have a substituentgroup, a C₁₋₆ alkoxy group which may have a substituent group, a C₂₋₆alkenyloxy group which may have a substituent group, a C₁₋₆ alkylthiogroup which may have a substituent group, a C₂₋₆ alkenylthio group whichmay have a substituent group, a C₂₋₆ alkynylthio group which may have asubstituent group, a substituted carbonyl group, an amino group whichmay have a substituent group, a C₁₋₆ alkylsulfonyl group which may havea substituent group, a C₂₋₆ alkenylsulfonyl group which may have asubstituent group, a C₂₋₆ alkynylsulfonyl group which may have asubstituent group, a C₁₋₆ alkylsulfinyl group which may have asubstituent group, a C₂₋₆ alkenylsulfinyl group which may have asubstituent group, a C₂₋₆ alkynylsulfinyl group which may have asubstituent group, a formyl group, a C₃₋₈ cycloalkyl group which mayhave a substituent group, a C₃₋₈ cycloalkenyl group which may have asubstituent group, a 5- to 14-membered non-aromatic heterocyclic groupwhich may have a substituent group, a C₆₋₁₄ aromatic hydrocarbon cyclicgroup which may have a substituent group and a 5- to 14-memberedaromatic heterocyclic group which may have a substituent group arepreferred; (2) one or more groups selected from 1) hydroxyl group, 2) ahalogen atom, 3) cyano group, 4) nitro group, 5) a C₁₋₆ alkyl group,C₂₋₆ alkenyl group or C₂₋₆ alkynyl group, each of which may besubstituted with at least one group selected from (i) hydroxyl group,(ii) cyano group, (iii) halogen atom, (iv) C₁₋₆ alkylamino group, (v)di(C₁₋₆ alkyl)amino group, (vi) C₂₋₆ alkenylamino group, (vii) di(C₂₋₆alkenyl)amino group, (viii) C₂₋₆ alkynylamino group, (ix) di(C₂₋₆alkynyl)amino group, (x) N-C₁₋₆ alkyl-N-C₂₋₆ alkenylamino group, (xi)N-C₁₋₆ alkyl-N-C₂₋₆ alkynylamino group, (xii) N-C₂₋₆ alkenyl-N-C₂₋₆alkynylamino group, (xiii) aralkyloxy group, (xiv) TBDMS oxy group, (xv)C₁₋₆ alkylsulfonylamino group, (xvi) C₁₋₆ alkylcarbonyloxy group, (xvii)C₂₋₆ alkenylcarbonyloxy group, (xviii) C₂₋₆ alkynylcarbonyloxy group,(xix) N-C₁₋₆ alkylcarbamoyl group, (xx) N-C₂₋₆ alkenylcarbamoyl groupand (xxi) N-C₁₋₆ alkynylcarbamoyl group, 6) a C₁₋₆ alkoxy group, C₂₋₆alkenyloxy group or C₂₋₆ alkynyloxy group, each of which may besubstituted with at least one group selected from (i) C₁₋₆ alkylaminogroup, (ii) aralkyloxy group and (iii) hydroxyl group, 7) a C₁₋₆alkylthio group, C₂₋₆ alkenylthio group or C₂₋₆ alkynylthio group, eachof which may be substituted with at least one group selected from (i)hydroxyl group, (ii) nitrile group, (iii) halogen atom, (iv) C₁₋₆alkylamino group, (v) aralkyloxy group, (vi) TBDMS oxy group, (vii) C₁₋₆alkylsulfonylamino group, (viii) C₁₋₆ alkylcarbonyloxy group and (ix)C₁₋₆ alkylcarbamoyl group, 8) a carbonyl group substituted with a groupselected from (i) C₁₋₆ alkoxy group, (ii) amino group, (iii) C₁₋₆alkylamino group, (iv) di(C₁₋₆ alkyl) amino group, (v) C₂₋₆ alkenylaminogroup, (vi) di(C₂₋₆ alkenyl) amino group, (vii) C₂₋₆ alkynylamino group,(vii) di (C₂₋₆ alkynyl) amino group, (viii) N-C₁₋₆ alkyl-N-C₂₋₆alkenylamino group, (ix) N-C₁₋₆ alkyl-N-C₂₋₆ alkynylamino group and (x)N-C₂₋₆ alkenyl-N-C₂₋₆ alkynylamino group, 9) an amino group which may besubstituted with one or two groups selected from (i) C₁₋₆ alkyl group,(ii) C₂₋₆ alkenyl group, (iii) C₂₋₆ alkynyl group, (iv) C₁₋₆alkylsulfonyl group, (v) C₂₋₆ alkenylsulfonyl group, (vi) C₂₋₆alkynylsulfonyl group, (vii) C₁₋₆ alkylcarbonyl group, (viii) C₂₋₆alkenylcarbonyl group and (ix) C₂₋₆ alkynylcarbonyl group, 10) a C₁₋₆alkylsulfonyl group, 11) a C₂₋₆ alkenylsulfonyl group, 12) a C₂₋₆alkynylsulfonyl group, 13) a C₁₋₆ alkylsulfinyl group, 14) a C₂₋₆alkenylsulfinyl group, 15) a C₂₋₆ alkynylsulfinyl group, 16) formylgroup, 17) a C₃₋₈ cycloalkyl group or C₃₋₈ cycloalkenyl group, each ofwhich may be substituted with at least one group selected from (i)hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) C₁₋₆ alkylgroup, (v) C₁₋₆ alkoxy group, (vi) C₁₋₆ alkoxy-C₁₋₆ alkyl group and(vii) aralkyl group, 18) a 5- to 14-membered non-aromatic heterocyclicgroup which may be substituted with at least one group selected from (i)hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) C₁₋₆ alkylgroup, (v) C₁₋₆ alkoxy group, (vi) C₁₋₆ alkoxy-C₁₋₆ alkyl group and(vii) aralkyl group, 19) a C₆₋₁₄ aromatic hydrocarbon cyclic group whichmay be substituted with at least one group selected from (i) hydroxylgroup, (ii) halogen atom, (iii) nitrile group, (iv) C₁₋₆ alkyl group,(v) C₁₋₆ alkoxy group, (vi) C₁₋₆ alkoxy-C₁₋₆ alkyl group and (vii)aralkyl group, and 20) a5- to 14-membered aromatic heterocyclic groupwhich may be substituted with at least one group selected from (i)hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) C₁₋₆ alkylgroup, (v) C₁₋₆ alkoxy group, (vi) C₁₋₆ alkoxy-C₁₋₆ alkyl group and(vii) aralkyl group are more preferred; and (3) one or more groupsselected from hydroxy group, a halogen atom (for example, fluorine atom,chlorine atom, bromine atom, iodine atom, etc.), cyano group, nitrogroup, a C₁₋₆ alkyl group (for example, methyl group, ethyl group,n-propyl group, iso-propyl group, n-butyl group, iso-butyl group,tert-butyl group, n-pentyl group, i-pentyl group, neopentyl group,n-hexyl group, etc.), a C₂₋₆ alkenyl group (for example, vinyl group,allyl group, 1-propenyl group, isopropenyl group, etc.), a C₂₋₆ alkynylgroup (for example, ethynyl group, 1-propynyl group, 2-propynyl group,butynyl group, pentynyl group, hexynyl group, etc.), a C₁₋₆ alkoxy group(methoxy group, ethoxy group, n-propoxy group, iso-propoxy group,n-butoxy group, etc.) and a C₂₋₆ alkenyloxy group (vinyloxy group,allyloxy group, 1-propenyloxy group, isopropenyloxy group, etc.) are themost preferred.

[0056] The preferable mode of the compound represented by the formula(I) above according to the present invention or a salt thereof is notparticularly limited, among which more preferable mode is a compound ora salt thereof, wherein R³ is a group represented by the formula:

[0057] (wherein R⁷ represents a group selected from the abovesubstituent group b; and ring A represents a nitrogen-containing6-membered ring which may be substituted with 1 to 4 groups selectedfrom the above substituent group b), and still more preferable mode is acompound represented by the formula:

[0058] (wherein R¹ represents cyano group, carboxyl group or anoptionally substituted carbamoyl group; R² represents hydrogen atom,hydroxyl group, a C₁₋₆ alkoxy group which may have a substituent group,a C₁₋₆ alkylthio group which may have a substituent group, a C₆₋₁₄aromatic hydrocarbon cyclic group which may have a substituent group ora 5- to 14-membered aromatic heterocyclic group which may have asubstituent group; R⁷ represents a group selected from the abovesubstituent group b; R⁸ represents a C₆₋₁₄ aromatic hydrocarbon cyclicgroup or a 5- to 14-membered aromatic heterocyclic group, each of whichmay have a substituent group; ring A represents a nitrogen-containing6-membered ring which may be substituted with 1 to 4 groups selectedfrom the substituent group b above) or a salt thereof. The preferablemode of each R¹, R⁷ and R⁸ are as described above.

[0059] In this specification, the “salt” is not particularly limitedinsofar as it forms a salt with the compound accroding to the presentinvenvention and is pharmacologically acceptable. Preferably, hydrogenhalides (for example, hydrofluoride, hydrochloride, hydrobromide andhydroiodide), inorganic acid salts (for example, sulfate, nitrate,perchlorate, phosphate, carbonate and bicarbonate), organic carboxylicacid salts (for example, acetate, trifluoroacetate, oxalate, maleate,tartrate, fumarate and citrate), organic sulfonic acid salts (forexample, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate,benzenesulfonate, toluenesulfonate and camphor sulfonate), amino acidsalts (for example, aspartate and glutamate), quaternary amine salts,alkali metal salts (for example, sodium salt and potassium salt),alkaline earth metal salts (for example, magnesium salt and calciumsalt), etc. may be proposed., and hydrochloride, oxalte etc. are morepreferred as the “pharmacologically acceptable salt”.

[0060] Production Process

[0061] A typical process for producing the compound according to thepresent invention represented by the above formula (I) will be shownbelow. Here, the “room temperature” mentioned below refers to 0 toaround 40° C.

[0062] Production Process 1

[0063] In the formula, R^(3a′) represents a 5- to 14-membered aromaticheterocyclic group which has a nitrogen atom at the 4-position and mayhave a substituent group (for example, 4-pyridyl group, 4-pyrimidinylgroup, 4-pyridazinyl group, etc.); R^(4a) represents a C₆₋₁₄ aromatichydrocarbon cyclic group which may have a substituent group or a 5- to14-membered aromatic heterocyclic group which may have a substituentgroup; and R⁹ represents a C₁₋₈ alkyl group. The 1,2-biaryl-1-ethanonecompound (ii)′ as the starting material of the compound represented bythe above formula (I) according to the present invention can be producedby reacting the aromatic carboxylate (i) with a 4-methyl aromaticheterocyclic compound represented by the formula R^(3a′)—CH₃ in thepresence of a base in a solvent, followed by dealcoholic condensation.The base used varies depending on the starting material, the solventused etc., and is not particularly limited so long as it is inert to thereaction. Preferably, secondary amine metal salts represented by lithiumbis(trimethylsilyl)amide and lithium diisopropylamide may be proposed.The solvent used varies depending on the starting material, reagentsetc., and is not particularly limited insofar as it is inert to thereaction and dissolves the starting material to a certain degree.Preferably, ethers such as tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol may be proposed. The reaction temperature is usually−78° C. to room temperature, preferably around 0° C.

[0064] Production Process 2

[0065] In the formula, R^(3a″) represents a C₆₋₁₄ aromatic hydrocarboncyclic group which may have a substituent group or a 5- to 14-memberedaromatic heterocyclic group which may have a substituent group; R^(4a)has the same meaning as defined above; and X¹ represents a halogen atom,an alkylsulfonyloxy group or an arylsulfonyloxy group. The1,2-biaryl-1-ethanone compound (ii)″ as the starting material forproducing the compound represented by the above formula (I) according tothe present invention can also be produced by Production Process 2instead of the above-mentioned Production Process 1. That is, it isproduced by allowing an aromatic trialkylsilyl cyanohydrin compoundprepared from the aromatic aldehyde (iii) to be condensed with acompound represented by the formula R^(3a)″—CH₂X¹ in the presence of abase; and then allowing a fluorine compound to act, followed bydecyanating trialkylsilylation. As the reagent used for preparing thearomatic trialkylsilyl cyanohydrin from (iii), using a trialkylsilylcyanide compound represented by trimethylsilyl cyanide is preferred. Inthis case, simultaneously using a metal salt such as zinc (II) iodide asa catalyst is also preferred, and it makes possible to achieve rapidreaction. The base used varies depending on the starting material, thesolvent used etc., and is not particularly limited so long as it isinert to the reaction. Preferably, secondary amine metal saltsrepresented by lithium bis(trimethylsilyl)amide and lithiumdiisopropylamide, etc. may be proposed. The fluorine compound usedvaries depending on the starting material, the solvent used etc., and isnot particularly limited so long as it is inert to the reaction.Preferably, hydrofluoric acid, hydrofluoride amine, and more preferablytetrabutylammonium fluoride may be proposed. The solvent used variesdepending on the starting material, reagents etc., and is notparticularly limited insofar as it is inert to the reaction anddissolves the starting material to a certain degree. Preferably, etherssuch as tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycolmay be proposed. The reaction temperature is preferably −78° C. to roomtemperature.

[0066] Production Process 3

[0067] In the formula, R^(3a) and R^(4a) represent a C₆₋₁₄ aromatichydrocarbon cyclic group which may have a substituent group or a 5- to14-membered aromatic heterocyclic group which may have a substituentgroup. The 3-(dimethylamino)-2-propen-1-one derivative (iv) is thestarting material for producing the compound (I) according to thepresent invention. (iv) can be produced by allowingN,N-dimethylformamide dimethylacetal to act on active methylene of (ii)produced in the above-mentioned Production Process 1 or 2. This reactionis carried out most preferably in the absence of a solvent, butpreferable results can be achieved even if it is carried out by dilutingwith a solvent which is inert to the reaction and dissolves the startingmaterial to a certain degree (for example, N,N-dimethylformamide,tetrahydrofuran, dioxane, N,N-methylpyrrolidone, benzene, toluene etc.),etc. The reaction temperature is usually room temperature to 120° C.,more preferably around 100° C.

[0068] Using the compounds obtained in the above-mentioned ProductionProcesses 1 to 3, the compound (vii) according to the present inventioncan be produced as follows.

[0069] Production Process 4

[0070] In the formula, R^(3a) and R^(4a) have the same meanings asdefined above; and X² represents a halogen atom. The compound (vii) canbe produced via the intermediates (v) and (vi) in this order from thecompound (iv) obtained in the above-mentioned Production Process 3(steps 4-(1) to 4-(3) in the formula). The2-oxo-1,2-dihydro-3-pyridylcarbonitrile derivative (v) can be producedby reacting (iv) with 2-cyanoacetamide in the presence of a base (step4-(1)). The base used varies depending on the starting material, thesolvent used etc., and is not particularly limited insofar as it isinert to the reaction. Preferably, an alkali metal alkoxide such assodium methoxide, sodium ethoxide or potassium tert-butoxide may beproposed. Further, also by using alkali metal carbonates such aspotassium carbonate or sodium carbonate, a preferable result can beobtained. The solvent used varies depending on the starting material,reagents etc., and is not particularly limited insofar as it is inert tothe reaction and dissolves the starting material to a certain degree.Preferably, N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, methanol, ethanol etc. may be proposed. The reactiontemperature is usually room temperature to 120° C., more preferablyaround 80° C. The 2-halogeno-3-pyridylcarbonitrile derivative (vi) canbe produced by converting an oxo group in (v) into a halogen atom (step4-(2)). The reaction is conducted preferably in the absence of asolvent. Further, when it is conducted by being suspending in a solventwhich is inert to the reaction and dissolves the starting material to acertain degree (for example, acetonitrile, dioxane, tetrahydrofuranetc.), a preferable result can be also obtained. The halogenating agentused for converting the oxo group into a halogen atom varies dependingon the starting material, the solvent used etc., and is not particularlylimited so long as it is inert to the reaction. Preferably, phosphorusoxychloride, phosphorus oxybromide etc. may be proposed. It ispreferably conducted by acting these halogenating agent at a reactiontemperature of 70 to 120° C. Further, when a tertiary amine such astripropylamine, a quaternary amine salt such as tetraethyl ammoniumchloride, or N,N-dimethylformamide etc., is added to this reactionsystem, the reaction is further promoted and a good result can beobtained. The 2-amino-3-pyridylcarbonitrile compound (vii) according tothe present invention can be produced by reacting X² (halogen atom) in(vi) with ammonia (step 4-(3)). The present reaction is carried outusually at 0 to 150° C., more preferably in an autoclave (50 to 100°C.). The solvent used varies depending on the starting material,reagents etc., and is not particularly limited insofar as it is inert tothe reaction and dissolves the starting material to a certain degree.Preferably, alcohols such as methanol or ethanol, ethers such astetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethylether, N,N-dimethylformamide, 1-methyl pyrrolidinone etc. may beproposed.

[0071] Production Process 5

[0072] In the formula, R^(3b) represents a C₆₋₁₄ aromatic hydrocarboncyclic group which may have a substituent group or a 5- to 14-memberedaromatic heterocyclic group which may have a substituent group; X³represents a halogen atom; and Y represents a C₁₋₆ alkyl group. The aryltin reagent (ix) used in the “step 6-(4)” in Production Process 6 can beproduced by lithiation of an aryl halide (viii); and then allowinghalogenotrialkyl tin to act. In the lithiation reaction, use of alkyllithium such as n-butyl lithium, sec-butyl lithium, tert-butyl lithiumetc. is preferred. The halogenotrialkyl tin used varies depending on thestarting material, the solvent used etc., and is not particularlylimited so long as it is inert to the reaction. Preferably, trimethyltinchloride such as chlorotributyltin, or triethyltin bromide etc. may beproposed. The solvent used varies depending on the starting material,reagents etc., and is not particularly limited insofar as it is inert tothe reaction and dissolves the starting material to a certain degree.Preferably, an ether such as tetrahydrofuran, diethyl ether etc. may beproposed. The reaction temperature is preferably −100° C. to roomtemperature.

[0073] When the 3-(dimethylamino)-2-propen-1-one derivative obtained bysubjecting the compound (acetylated aryl or acetylated heteroarylrepresented by the formula R^(4a)—COCH₃) wherein R^(3a) in (ii) wasreplaced by a hydrogen atom to the reaction in Production Process 3, isfurther subjected to “step 4-(1)” in Production Process 4, the compound(x) wherein R^(3a) in (v) was replaced by a hydrogen atom is obtained.The method of producing the compound (xiv) according to the presentinvention from the compound (x) is shown below.

[0074] Production Process 6

[0075] In the formula, R^(3b) and R^(4a) have the same meanings asdefined above; and X⁴ represents a halogen atom. The compound (xiv)according to the present invention can be produced from (x) throughsteps 6-(1) to 6-(4) (intermediates (xi) to (xiii)). The compound (xi)can be produced by alkylating an oxygen atom at the 2-position in (x)with 2-halogenoacetamide in the presence of a base (step 6-(1)). The2-halogenoacetamide used varies depending on the starting material, thesolvent used etc., and is not particularly limited so long as it isinert to the reaction. The reaction conducted by using 2-chloroacetamideis preferred, and conducted by further adding sodium iodide is morepreferred. The base used varies depending on the starting material, thesolvent used etc., and is not particularly limited so long as it isinert to the reaction. Preferably, sodium hydride, sodium hydroxide,potassium hydroxide, sodium bicarbonate, sodium carbonate and potassiumcarbonate may be proposed. The solvent used varies depending on thestarting material, reagents etc., and is not particularly limitedinsofar as it is inert to the reaction and dissolves the startingmaterial to a certain degree. Preferably, ketones such as acetone ormethyl ethyl ketone, alcohols such as methanol or ethanol, ethers suchas tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycoldimethyl ether, N,N-dimethylformamide, dimethyl sulfoxide, 1-methylpyrrolidinone etc. may be proposed. The reaction temperature is usually0 to 100° C. The compound (xii) can be produced by transaminating the2-aminocarbonylmethyloxy-3-cyanopyridine derivative (xi) in the presenceof a base in a solvent (step 6-(2)). The base used varies depending onthe starting material, the solvent used etc., and is not particularlylimited so long as it is inert to the reaction. Preferably, sodiumhydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate,sodium carbonate, potassium carbonate etc. may be proposed. The solventused varies depending on the starting material, reagents etc. and is notparticularly limited insofar as it is inert to the reaction anddissolves the starting material to a certain degree. Preferably, ketonessuch as acetone or methyl ethyl ketone, alcohols such as methanol,ethanol, propanol or butanol, ethers such as tetrahydrofuran, dioxane,dimethoxyethane or diethylene glycol dimethyl ether,N,N-dimethylformamide, dimethyl sulfoxide, 1-methyl pyrrolidinone etc.may be proposed. The reaction temperature is usually room temperature to150° C. The compound (xiii) can be produced by halogenating the5-position of the pyridine ring in the 2-aminonicotinonitrile derivative(xii) with a halogenating agent in a solvent (step 6-(3)). As thehalogenating agent used, N-bromosuccinimide, bromine etc. are preferred.The solvent used varies depending on the starting material, reagentsetc., and is not particularly limited insofar as it is inert to thereaction and dissolves the starting material to a certain degree.Preferably, alcohols such as methanol or ethanol, ethers such astetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethylether, N,N-dimethylformamide, 1-methyl pyrrolidinone etc. may beproposed. The reaction temperature is usually −20° C. to roomtemperature. The compound (xiv) according to the present invention canbe produced by allowing the aryl tin reagent obtained in ProductionProcess 5 to act on the 2-amino-5-halogenonicotinonitrile derivative(xiii) in the presence of a palladium catalyst in a solvent to introducean aromatic group into the 5-position of the pyridine ring in (xiii)(step 6-(4)). The palladium catalyst used varies depending on thestarting material, the solvent used etc., and is not particularlylimited so long as it is inert to the reaction. Preferably,dichlorobis(triphenylphoshine) palladium (II), palladium (II) acetate,tetrakis(triphenylphosphine) palladium (0), tris(dibenzylidene acetone)dipalladium (0) etc. may be proposed. The solvent used varies dependingon the starting material, reagents etc., and is not particularly limitedinsofar as it is inert to the reaction and dissolves the startingmaterial to a certain degree. Preferably, alcohols such as methanol orethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether, toluene, xylene,N,N-dimethylformamide, 1-methyl pyrrolidinone etc. may be proposed. Thereaction temperature is usually room temperature to 150° C.

[0076] Out of the compounds represented by the above formula (I)according to the present invention, those compounds wherein R², R³and/or R⁴ represent an α-hydroxy nitrogen-containing aromaticheterocyclic group having a hydroxyl group at the α-position of thenitrogen atom can be produced as follows.

[0077] For example, the compound (xvi) having an α-hydroxynitrogen-containing aromatic heterocyclic group at the 5-position of thepyridine ring can be produced by hydrolysis of the α-alkoxynitrogen-containing aromatic heterocyclic compound (xv).

[0078] Production Process 7

[0079] In the formula, R^(4a) has the same meaning as defined above; R¹⁰represents a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynylgroup etc.; the ring A¹ represents a pyridinyl group, pyrimidyl groupand pyrazinyl group; and the ring A² represents a dihydrooxopyridinylgroup, a dihydrooxopyrimidyl group, a dihydropyrazinyl group or atetrahydropyrazinyl group. The reaction is carried out preferably in anaqueous solution of a mineral acid such as, for example, hydrochloricacid, hydrobromic acid or sulfuric acid, or in a mixed solvent of theabove-mentioned aqueous solution of the mineral acid and acetic acid.The reaction temperature is usually room temperature to 100° C.

[0080] Further, a substituent can be introduced into the α-hydroxynitrogen-containing aromatic heterocyclic ring in the compound (xvi)according to the present invention obtained by the above-mentionedProduction Process 7, by the following method.

[0081] Production Process 8

[0082] In the formula, R^(4a) and ring A² have the same meanings asdefined above; R¹¹ represents a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group,a C₂₋₆ alkynyl group etc.; and X⁵ represents a halogen atom. Accordingto this process, (xvi) is reacted with an alkyl halide compound etc. inthe presence of a base in a solvent, whereby the compound (xvii) havinga substituent group introduced into the nitrogen atom on the ring A² canbe produced. The base used varies depending on the starting material,the solvent used etc., and is not particularly limited so long as it isinert to the reaction. Preferably, sodium hydride, sodium hydroxide,potassium hydroxide, sodium bicarbonate, sodium carbonate and potassiumcarbonate may be proposed. The solvent used varies depending on thestarting material, reagents etc., and is not particularly limitedinsofar as it is inert to the reaction and dissolves the startingmaterial to a certain degree. Preferably, alcohols such as methanol orethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether, N,N-dimethylformamide, dimethylsulfoxide, 1-methyl pyrrolidinone, etc. may be proposed. The reactiontemperature is usually 0 to 100° C.

[0083] Production Process 9

[0084] In the formula, R^(3a), R^(4a) and X⁴ have the same meanings asdefined above; and R^(2a) represents a C₆₋₁₄ aromatic hydrocarbon cyclicgroup which may have a substituent group or a 5- to 14-membered aromaticheterocyclic group which may have a substituent group. The compound(xxv) according to the present invention can be produced from (xviii)and (xix) through steps 9-(1) to 9-(6) (intermediates (xx) to (xxiv)).The compound (xx) can be produced by dehydrating condensation of (xviii)and (xix) in the presence of a base (step 9-(1)). The base used in thereaction varies depending on the starting material, the solvent usedetc., and is not particularly limited so long as it is inert to thereaction. Preferably, inorganic salts such as potassium hydroxide orsodium hydroxide may be proposed. The solvent used varies depending onthe starting material, reagents etc., and is not particularly limitedinsofar as it is inert to the reaction and dissolves the startingmaterial to a certain degree. Preferably, a mixed solvent of an alcoholsuch as ethanol and water may be proposed. The2-oxo-1,2-dihydro-3-pyridylcarbonitrile derivative (xxi) can be producedby reacting (xx) with 2-cyanoacetamide in the presence of a base (step9-(2)). The reaction can be promoted in an oxygen atmosphere. The baseused varies depending on the starting material, the solvent used etc.,and is not particularly limited insofar as the reaction is notinhibited. Preferably, an alkali metal alkoxide such as sodiummethoxide, sodium ethoxide or potassium tert-butoxide may be proposed.Otherwise, using alkali metal carbonates such as potassium carbonate orsodium carbonate can also bring about a preferable result. The solventused varies depending on the starting material, reagents etc., and isnot particularly limited insofar as it is inert to the reaction anddissolves the starting material to a certain degree. Preferably,N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide,methanol, ethanol etc. may be proposed. The reaction temperature ispreferably room temperature to 120° C., more preferably around roomtemperature. The compound (xxii) can be produced by alkylating an oxygenatom at the 2-position in (xxi) with 2-halogenoacetamide in the presenceof a base (step 9-(3)). The 2-halogenoacetamide used varies depending onthe starting material, the solvent used etc., and is not particularlylimited so long as it is inert to the reaction. The reaction conductedby using 2-chloroacetamide is preferred, and conducted by further addingsodium iodide is more preferred. The base used varies depending on thestarting material, the solvent used etc., and is not particularlylimited so long as it is inert to the reaction. Preferably, sodiumhydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate,sodium carbonate and potassium carbonate may be proposed. The solventused varies depending on the starting material, reagents etc., and isnot particularly limited insofar as it is inert to the reaction anddissolves the starting material to a certain degree. Preferably, ketonessuch as acetone or methyl ethyl ketone, alcohols such as methanol orethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane ordiethylene glycol dimethyl ether, N,N-dimethylformamide, dimethylsulfoxide, 1-methyl pyrrolidinone etc. may be proposed. The reactiontemperature is usually 0 to 100° C. The compound (xxiii) can be producedby transaminating the 2-aminocarbonylmethyloxy-3-cyanopyridinederivative (xxii) in the presence of a base in a solvent (step 9-(4)).The base used varies depending on the starting material, the solventused etc., and is not particularly limited so long as it is inert to thereaction. Preferably, for example, sodium hydride, sodium hydroxide,potassium hydroxide, sodium bicarbonate, sodium carbonate, potassiumcarbonate etc. may be proposed. The solvent used varies depending on thestarting material, reagents etc., and is not particularly limitedinsofar as it is inert to the reaction and dissolves the startingmaterial to a certain degree. Preferably, N,N-dimethylformamide,dimethyl sulfoxide, 1-methylpyrrolidinone etc. may be proposed, otherthan ketones such as acetone or methyl ethyl ketone, alcohols such asmethanol, ethanol, propanol or butanol, ethers such as tetrahydrofuran,dioxane, dimethoxyethane or diethylene glycol dimethyl ether maybeproposed. The reaction temperature is usually room temperature to 150°C. The compound (xxiv) can be produced by halogenating the 5-position ofthe pyridine ring in the 2-aminonicotinonitrile derivative (xxiii) witha halogenating agent in a solvent (step 9-(5)). The halogenating agentused varies depending on the starting material, the solvent used etc.,and is not particularly limited so long as it is inert to the reaction.Preferably, N-bromosuccinimide, bromine etc. may be proposed. Further,the solvent used varies depending on the starting material, reagentsetc., and is not particularly limited insofar as it it inert to thereaction and dissolves the starting material to a certain degree.Preferably, alcohols such as methanol or ethanol, ethers such astetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethylether, N,N-dimethylformamide, 1-methyl pyrrolidinone etc. may beproposed. The reaction temperature is usually −20° C. to roomtemperature. The compound (xxv) according to the present invention canbe produced by reacting the 2-amino-5-halogenonicotinonitrile derivative(xxiv) with the aryl tin reagent obtained in Production Process 5 in thepresence of a palladium catalyst in a solvent, to introduce an aromaticgroup into the 5-position of the pyridine ring in (xxiv) (step 9-(6)).The palladium catalyst used varies depending on the starting material,the solvent used etc., and is not particularly limited so long as it isinert to the reaction. Preferably, dichlorobis (triphenylphoshine)palladium (II), palladium (II) acetate, tetrakis(triphenylphosphine)palladium (0), tris(dibenzylidene acetone) dipalladium (0), dichlorobis(acetonitrile) palladium (II) etc. may be proposed. Further, the solventused varies depending on the starting material, reagents etc., and isnot particularly limited insofar as it is inert to the reacton anddissolves the starting material to a certain degree. Preferably,alcohols such as methanol, ethanol, propanol or butanol, ethers such astetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethylether, toluene, xylene, N, N-dimethylformamide, 1-methyl pyrrolidinoneetc. may be proposed The reaction temperature is usually roomtemperature to 150° C.

[0085] Production Process 10

[0086] In the formula, R^(3a), R^(4a) and X⁴ have the same meanings asdefined above; R^(2b) represents an optionally substituted alkyl group;and Y represents a lower alkyl group. The compound (xxxiii) according tothe present invention can be produced from (xxvi) and (xix) throughsteps 10-(1) to 10-(7) (intermediates (xxvii) to (xxxii)). The compound(xxvii) can be produced by condensation of (xxvi) with (xix) (step10-(1)). The base used varies depending on the starting material, thesolvent used etc., and is not particularly limited so long as it isinert to the reaction. Preferably, potassium tert-butoxide etc. may beproposed. The solvent used varies depending on the starting material,reagents etc., and is not particularly limited insofar as it is inert tothe reaction and dissolves the starting material to a certain degree.tert-Butanol is preferred. The reaction temperature is preferably roomtemperature to 120° C., more preferably around room temperature. Thecompound (xxxviii) can be produced by alkylating (xxvii) with methylhalide in the presence of a base (step 10-(2)). The base used in thereaction varies depending on the starting material, the solvent usedetc., and is not particularly limited so long as it is inert to thereaction. Preferably, an inorganic base such as potassium carbonate etc.may be proposed. Preferable example of the methyl halide is methyliodide. The solvent used varies depending on the starting material,reagents etc., and is not particularly limited insofar as it is inert tothe reaction and dissolves the starting material to a certain degree.Preferably, a ketone such as acetone or methyl ethyl ketone may beproposed. The reaction temperature is preferably room temperature to 12°C, more preferably around room temperature. The2-oxo-1,2-dihydro-3-pyridyl carbonitrile derivative (xxix) can beproduced by reacting (xxviii) with 2-cyanoacetamide in the presence of abase (step 10-(3)). The base used varies depending on the startingmaterial, the solvent used etc., and is not particularly limited so longas it is inert to the reaction. Preferably, an alkali metal alkoxidesuch as sodium methoxide, sodium ethoxide, sodium isopropoxide,potassium tert-butoxide etc. may be proposed. The solvent used variesdepending on the starting material, reagents etc., and is notparticularly limited insofar as it is inert to the reaction anddissolves the starting material to a certain degree. Preferably,N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide,isopropanol etc. The reaction temperature is preferably 0° C. to 120° C.The compound (xxx) can be produced by alkylating an oxygen atom at the2-position of (xxix) with 2-halogenoacetamide in the presence of a base(step 10-(4)) As the 2-halogenoacetamide used, 2-chloroacetamide ispreferred, and the reaction in which sodium iodide is further added ismore preferred. The base used varies depending on the starting material,the solvent used etc., and is not particularly limited so long as it isinert to the reaction. Preferably, sodium hydride, sodium hydroxide,potassium hydroxide, sodium bicarbonate, sodium carbonate and potassiumcarbonate may be proposed. The solvent used varies depending on thestarting material, reagents etc., and is not particularly limited solong as it is inert to the reaction and dissolves the starting materialto a certain degree. Preferably, ketones such as acetone or methyl ethylketone, alcohols such as methanol or ethanol, ethers such astetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethylether, N,N-dimethylformamide, dimethyl sulfoxide, 1-methylpyrrolidinone, etc. may be proposed. The reaction temperature is usually0 to 100° C. The compound (xxxi) can be produced by transaminating the2-aminocarbonylmethyloxy-3-cyanopyridine derivative (xxx) in thepresence of a base in a solvent (step 10-(5)). The base used variesdepending on the starting material, the solvent used etc., and is notparticularly limited so long as it is inert to the reaction. Preferably,sodium hydride, sodium hydroxide, potassium hydroxide, sodiumbicarbonate, sodium carbonate, potassium carbonate etc. may be proposed.The solvent used varies depending on the starting material, the solventused etc., and is not particularly limited unless it is inert to thereaction. Preferably, ketones such as acetone or methyl ethyl ketone,alcohols such as methanol, ethanol, propanol or butanol, ethers such astetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethylether, N,N-dimethylformamide, dimethyl sulfoxide, 1-methylpyrrolidinone, etc. may be proposed. The reaction temperature is usuallyroom temperature to 150° C. The compound (xxii) can be produced byhalogenating the 5-position of the pyridine ring in the2-aminonicotinonitrile derivative (xxxi) with a halogenating agent in asolvent (step 10-(6)). The halogenating agent used varies depending onthe starting material, the solvent used etc., and is not particularlylimited so long as it is inert to the reaction. Preferably,N-bromosuccinimide, bromine etc. may be proposed. The solvent usedvaries depending on the starting material, reagents etc., and is notparticularly limited insofar as it is inert to the reaction anddissolves the starting material to a certain degree. Preferably,alcohols such as methanol or ethanol etc., ethers such astetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethylether etc., N,N-dimethylformamide, 1-methyl pyrrolidinone etc. may beproposed. The reaction temperature is usually −20° C. to roomtemperature. The compound (xxxiii) according to the present inventioncan be produced by allowing the aryl tin reagent obtained in ProductionProcess 5 to act on the 2-amino-5-halogenonicotinonitrile derivative(xxxii) in the presence of a palladium catalyst in a solvent, tointroduce an aromatic group into the 5-position of the pyridine ring in(xxxii) (step 10-(7)). As the palladium catalyst used is, for example,dichlorobis(triphenylphoshine) palladium (II), palladium (II) acetate,tetrakis(triphenylphosphine) palladium (0), tris(dibenzylidene acetone)dipalladium (0), dichlorobis(acetonitrile) palladium (II) etc. arepreferred. The solvent used varies depending on the starting material,reagents etc., and is not particularly limited insofar as it is inert tothe reaction and dissolves the starting material to a certain degree.Preferably, alcohols such as methanol or ethanol, ethers such astetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethylether, toluene, xylene, N,N-dimethylformamide, 1-methyl pyrrolidinoneetc. may be proposed. The reaction temperature is usually roomtemperature to 150° C.

[0087] Production Process 11

[0088] In the formula, R^(2a) and R^(4a) have the same meanings asdefined above; R¹⁰ represents a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group,a C₂₋₆ alkynyl group etc.; the ring A¹ represents a pyridinyl group, apyrimidyl group or a pyrazinyl group; and the ring A² represents adihydrooxopyridinyl group, a dihydrooxopyrimidyl group, adihydropyrazinyl group or a tetrahydropyrazinyl group. The compound(xxxv) having an α-hydroxy nitrogen-containing aromatic heterocyclicgroup at the 5-position of the pyridine ring can be produced byhydrolyzing the α-alkoxy nitrogen-containing aromatic heterocycliccompound (xxxiv). The solvent used in this reaction varies depending onthe starting material, reagents etc., and is not particularly limitedinsofar as it is inert to the reaction and dissolves the startingmaterial to a certain degree. Preferably, an aqueous solution of amineral acid such as hydrochloric acid, hydrobromic acid or sulfuricacid, or a mixed solvent of the above-mentioned aqueous solution of themineral acid and acetic acid may be proposed. The reaction temperatureis usually room temperature to 100° C.

[0089] Production Process 12

[0090] In the formula, R^(2b), R^(4a), the ring A¹ and the ring A² havethe same meanings as defined above; and R¹⁰ represents a C₁₋₆ alkylgroup, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl group, etc. The compound(xxxvii) having an α-hydroxy nitrogen-containing aromatic heterocyclicgroup at the 5-position of the pyridine ring can be produced byhydrolyzing the α-alkoxy nitrogen-containing aromatic heterocycliccompound (xxxvi). The solvent used in this reaction varies depending onthe starting material, reagents etc., and is not particularly limitedinsofar as it is inert to the reaction and dissolves the startingmaterial to a certain degree. Preferably, an aqueous solution of amineral acid such as hydrochloric acid, hydrobromic acid or sulfuricacid, or a mixed solvent of the above-mentioned aqueous solution of themineral acid and acetic acid may be proposed. The reaction temperatureis usually room temperature to 100° C.

[0091] Production Process 13

[0092] In the formula, R^(2c) represents hydrogen atom, hydroxyl group,a C₁₋₆ alkoxy group which may have a substituent group, a C₁₋₆ alkylgroup which may have a substituent group, a C₆₋₁₄ aromatic hydrocarboncyclic group which may have a substituent group or a 5- to 14-memberedaromatic heterocyclic group which may have a substituent group; R^(3c)represents a C₆₋₁₄ aromatic hydrocarbon cyclic group which may have asubstituent group or a 5- to 14-membered aromatic heterocyclic groupwhich may have a substituent group; and R^(4a) and X⁴ have the samemeanings as defined above. The compound (xxviii) according to thepresent invention can be produced by reacting the2-amino-5-halogenonicotinonitrile derivative (xxxix) with an aryl boronreagent or an aryl tin reagent in the presence of a palladium catalystand a base in a solvent, to introduce an aromatic group into the5-position of the pyridine ring in (xxxix). The palladium catalyst usedvaries depending on the starting material, the solvent used etc., and isnot particularly limited so long as it is inert to the reaction.Preferably, dichlorobis(triphenylphoshine) palladium (II), palladium(II) acetate, tetrakis(triphenylphosphine) palladium (0),tris(dibenzylidene acetone) dipalladium (0), dichlorobis(acetonitrile)palladium (II) etc. may be proposed. The base used varies depending onthe starting material, the solvent used, etc., and is not particularlylimited so long as it is inert to the reaction. Preferably, an inorganicbase such as potassium carbonate or calcium phosphate, or an organicamine such as ethyl diisopropyl amine may be proposed. The solvent usedvaries depending on the starting material, reagents etc., and is notparticularly limited insofar as it is inert to the reaction anddissolves the starting material to a certain degree. Preferably,alcohols such as methanol or ethanol, ethers such as tetrahydrofuran,dioxane, dimethoxyethane, diethylene glycol or dimethyl ether, toluene,xylene, N,N-dimethylformamide, 1-methyl pyrrolidinone etc. may beproposed. The reaction temperature is usually room temperature to 150°C.

[0093] Production Process 14

[0094] In the formula, R^(3d) represents a C₆₋₁₄ aromatic hydrocarboncyclic group which may have a substituent group, a 5- to 14-memberedaromatic heterocyclic group which may have a substituent group or a 5-to 14-membered non-aromatic heterocyclic group which may have asubstituent group; and R^(2c) and R^(4a) have the same meanings asdefined above. The compound (xli) according to the present invention canbe produced by hydrolyzing the cyano group of the compound (xl) in thepresence of a base in a solvent. The base used varies depending on thestarting material, the solvent used etc., and is not particularlylimited so long as it is inert to the reaction. Preferably, an inorganicbase such as sodium hydroxide or potassium hydroxide may be proposed.The solvent used varies depending on the starting material, reagentsetc., and is not particularly limited insofar as it is inert to thereacton and dissolves the starting material to a certain degree.Preferably, alcohols such as methanol or ethanol, or a mixture of suchalcohols and water. The reaction temperature is usually room temperatureto 150° C.

[0095] Production Process 15

[0096] In the formula, R^(1b) represents a carbamoyl group which mayhave a substituent group; and R^(2c), R^(3d) and R^(4a) have the samemeanings as defined above. The carbamoyl derivative (xlii) according tothe present invention can be produced by dehydrating condensation of thecarboxylic acid derivative (xli) with an amine in the presence of acondensing agent in a solvent. As the condensing agent used,3-(3-dimethylaminopropyl)-1-ethylcarbodiimide etc. are preferred. Thereaction is promoted by adding 1-hydroxybenzotriazole etc. When theamine to be condensed with the carboxylic acid has formed a salt withhydrogen chloride etc., a suitable amount of tertiary amine such astriethylamine is added. As the solvent used, for example, ethers such astetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol,N,N-dimethylformamide, 1-methyl pyrrolidinone etc. are preferred. Thereaction temperature is usually 0 to 50° C., and more preferably aroundroom temperature.

[0097] Production Process 16

[0098] In the formula, R^(2d) represents hydrogen atom, a C₁₋₆ alkoxygroup which may have a substituent group, a C₁₋₆ alkyl group which mayhave a substituent group, a C₆₋₁₄ aromatic hydrocarbon cyclic groupwhich may have a substituent group or a 5- to 14-membered aromaticheterocyclic group which may have a substituent group; the ring A³represents pyridinyl group, pyrimidyl group or pyrazinyl group; R¹¹represents a C₁₋₆ alkyl group which may have a substituent group, a C₂₋₆alkenyl group which may have a substituent group or a C₂₋₆ alkynyl groupwhich may have a substituent group; X⁵ represents an eliminating groupsuch as a halogen atom or a sulfonate group which may have a substituentgroup; and R^(4a) and ring A² have the same meanings as defined above,respectively. The compounds (xliv) and (xlv) according to the presentinvention can be produced by reacting the compound (xliii) with R⁹-X⁵ inthe presence of a base in a solvent. The base used varies depending onthe starting material, the solvent used etc., and is not particularlylimited so long as it is inert to the reaction. Preferably, inorganicbases represented by potassium carbonate, potassium bicarbonate andsodium carbonate may be proposed. The solvent generally used variesdepending on the starting material, reagents etc., and is notparticularly limited insofar as it it inert to the reacton and dissolvesthe starting material to a certain degree. Preferably, an amide such asN,N-dimethylformamide may be proposed. The reaction temperature ispreferably room temperature to 100° C., and more preferably around 65°C.

[0099] Production Process 17

[0100] In the formula, R¹² represents a C₆₋₁₄ aromatic hydrocarboncyclic group which may have a substituent group or a 5- to 14-memberedaromatic heterocyclic group which may have a substituent group; andR^(2c), R^(4a) and ring A² have the same meanings as defined above,respectively. The compound (xlvii) according to the present inventioncan be produced by reacting the compound (xlvi) with an aryl boronreagent in the presence of a base and a copper catalyst in a solvent.The base used in the reaction varies depending on the starting material,the solvent used etc., and is not particularly limited insofar as it isinert to the reaction. Preferably, a tertiary amine such as pyridine,diisopropyl ethylamine, triethylamine etc. may be proposed. The coppercatalyst used varies depending on the starting material, the solventused etc., and is not particularly limited insofar as it is inert to thereaction. Preferably, divalent copper such as copper acetate, copperbromide, copper sulfate etc. may be proposed, and copper acetate is morepreferred. The solvent used varies depending on the starting material,reagents etc., and is not particularly limited insofar as it is inert tothe reaction and dissolves the starting material to a certain degree.Preferably, N,N-dimethylformamide, tetrahydrofuran, ethyl acetate etc.may be proposed. The reaction temperature is preferably around roomtemperature.

[0101] The foregoing is a typical example of the method of producing thecompound (I) according to the present invention, and the startingcompound in production of the compound of the present invention may forma salt or a hydrate and is not particularly limited so long as it isinert to the reaction. Further, when the compound (I) according to thepresent invention is obtained in a free form, it can be converted into asalt which may be formed by the above-mentioned compound (I), in a usualmanner. Further, the various resulting isomers (for example, geometricisomer, optical isomer based on asymmetric carbon, rotational isomer,stereoisomer and tautomer) of the compound (I) according to the presentinvention can be purified and isolated by using usual separating means,for example, re-crystallization, diastereomer salt method, enzymefractionation method, and various kinds of chromatography (for example,thin layer chromatography, column chromatography and gaschromatography).

[0102] The compound represented by the above formula (I) according tothe present invention, a salt thereof or a hydrate of them can be formedinto a pharmaceutical preparation by a conventional method. As thepreferable preparation forms, tablets, powders, fine granules, granules,coated tablets, capsules, syrups, troches, inhalations, suppositories,injections, ointments, eye ointments, eye drops, nose drops, ear drops,poultices, lotions etc. may be proposed. In pharmaceuticalmanufacturing, ordinarily used fillers, binders, disintegrating agents,lubricants, coloring agents, flavoring agents, and as necessarystabilizers, emulsifiers, absorption promoters, surfactants, pHadjusters, preservatives and antioxidants may be used, and it may beprepared in a conventional method by blending ingredients generally usedas starting materials for pharmaceutical preparations. As theseingredients, for example, (1) animal and vegetable oils such as soybeanoil, tallow or synthetic glyceride; (2) hydrocarbons such as liquidparaffin, squalane or solid paraffin; (3) ester oils such asoctyldodecyl myristate or isopropyl myristate; (4) higher alcohols suchas cetostearyl alcohol or behenyl alcohol; (5) silicon resin; (6)silicon oil; (7) surfactants such as polyoxyethylene fatty ester,sorbitan fatty ester, glycerin fatty ester, polyoxyethylene sorbitanfatty ester, polyoxyethylene hydrogenated castor oil orpolyoxyethylene-polyoxypropylene block copolymer; (8) water-solublepolymers such as hydroethyl cellulose, polyacrylic acid, carboxyvinylpolymer, polyethylene glycol, polyvinylpyrrolidone or methyl cellulose;(9) lower alcohols such as ethanol or isopropanol; (10) polyhydricalcohols such as glycerin, propylene glycol, dipropylene glycol orsorbitol; (11) sugars such as glucose or sucrose; (12) inorganic powdersuch as silicic anhydride, aluminum magnesium silicate or aluminumsilicate; and (13) pure water may be proposed. 1) As the fillers, forexample, lactose, corn starch, white sugar, glucose, mannitol, sorbitol,crystalline cellulose, silicon dioxide etc.; 2) as the binders, forexample, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethylcellulose, arabic gum, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone,polypropylene glycol-polyoxyethylene block polymer, megulumin, calciumcitrate, dextrin, pectin etc.; 3) as the disintegrating agents, forexample, starch, agar, gelatin powder, crystalline cellulose, calciumcarbonate, sodium bicarbonate, calcium citrate, dextrin, pectin,carboxymethyl cellulose calcium etc.; 4) as the lubricants, for example,magnesium stearate, talc, polyethylene glycol, silica, hardenedvegetable oil etc.; 5) as the coloring agents, any of which are approvedto be added to pharmaceutical preparations; 6) as the flavoring agents,cocoa powder, menthol, aromatic powder, peppermint oil, borneol,cinnamon powder etc.; and 7) as the antioxidants, those which areapproved to be added to pharmaceutical preparations, such as ascorbicacid, α-tocopherol etc., maybe used, respectively.

[0103] 1) The oral preparation is produced by mixing the compoundaccording to the present invention or a salt thereof with fillers and ifnecessary with a binder, a disintegrating agent, a lubricant, a coloringagent, a flavoring agent etc., and then forming it in a usual mannerinto powders, fine granules, granules, tablets, coated tablets,capsules, etc. 2) The tablets and granules may be coated with a sugar orgelatin coating or if necessary with another suitable coating. 3) Theliquid preparations such as syrups, injections and eye drops areprepared by mixing the active agent with a pH adjuster, a solubilizerand an isotonizing agent etc., and with a solubilizing aid, astabilizer, a buffer, a suspension agent, an antioxidant etc. ifnecessary, followed by forming it into a preparation in a usual manner.The liquid preparation may be formed into a freeze-dried product and theinjection can be administered intravenously, subcutaneously orintramuscularly. Preferable examples of the suspension agent includemethyl cellulose, Polysorbate 80, hydroxyethyl cellulose, arabic gum,tragacanth powder, sodium carboxymethyl cellulose, polyoxyethylenesorbitan monolaurate etc.; preferable examples of the solubilizing aidinclude polyoxyethylene hardened castor oil, Polysorbate 80,nicotinamide, polyoxyethylene sorbitan monolaurate etc.; preferableexamples of the stabilizer include sodium sulfite, sodium metasulfite,ether etc.; preferable examples of the preservative include methylp-oxybenzoate, ethyl p-oxybenzoate, sorbic acid, phenol, cresol,chlorocresol etc. 4) The agent for external application can be producedin any conventional method. That is, the starting base material can makeuse of various starting materials ordinarily used in pharmaceuticalpreparations, quasi-drug, cosmetics, etc. For example, the materialincludes animal and vegetable oils, mineral oil, ester oil, waxes,higher alcohols, fatty acids, silicon oil, surfactants, phospholipids,alcohols, polyvalent alcohols, water-soluble polymers, clay minerals,pure water etc. If necessary, a pH adjuster, an antioxidant, a chelatingagent, a preservative, a coloring agent, a perfume etc. can further beadded. Further, ingredients having a differentiation-inducing action, ablood-stream promoting agent, a sterilizer, an antiinflammatory agent, acell activator, vitamins, amino acids, a humectant, a keratinsolubilizer etc. can also be incorporated as necessity.

[0104] Although the dose of the medicament according to the presentinvention varies depending on severeness of symptoms, age, sex, bodyweight, administration form, type of salt, chemical sensitivity, type ofdisease etc., it is given daily in one portion or in divided portions toan adult in a dose of usually about 30 μg to 10 g, preferably 100 μg to5 g, more preferably 100 μg to 100 mg for oral administration, or about30 μg to 1 g, preferably 100 μg to 500 mg, more preferably 100 μg to 30mg for injection.

[0105] According to the present invention, a novel 2-aminopyridinecompound could be provided. The compounds according to the presentinvention or a salt thereof have an excellent antagonistic action on anadenosine receptor (adenosine A₁, A_(2a), A_(2b) or A₃ receptor), andare excellent as an antagonist for an adenosine A₂ receptor,particularly for an adenosine A_(2B) receptor. The compounds accordingto the present invention or a salt thereof are useful as an agent fortreating or preventing a disease to which an adenosine receptor(adenosine A₁, A_(2a), A_(2b) or A₃ receptor) relates, and a diseaseagainst which an antagonist for the receptor is efficacious. Thecompound according to the present invention or a salt thereof is usefulnot only as an agent for treating, preventing or improving constipation,irritable bowel syndrome, constipation accompanying irritable bowelsyndrome, organic constipation, constipation accompanyingenteroparalytic ileus, constipation accompanying congenital digestivetract dysfunction, constipation accompanying ileus, diabetes, diabeticcomplications, diabetic retinopathy, obesity, asthma etc., but alsouseful as a hypoglycemic agent, an improving agent for impaired glucosetolerance, a potentiating agent for insulin sensitivity, hypotensiveagent, a diuretic, a therapeutic agent for osteoporosis, ananti-Parkinson's disease agent, an anti-Alzheimer's disease agent, atherapeutic agent for inflammatory intestinal diseases, a therapeuticagent for Crohn's disease, etc.

EXAMPLES

[0106] Reference Examples, Examples and Test Examples shown below aredescribed merely for illustrative purposes, and the compounds of theinvention are not limited to the following specific examples in anycase. The present invention can be carried out to the maximum by thoseskilled in the art by making various modifications not only to thefollowing examples but also to the claims in the present specification,and such modifications fall under the claims of the present application.

Reference Example 1

[0107] 1-(2-Furyl)-2-(4-pyridyl)-1-ethanone

[0108] In a nitrogen atmosphere, lithium bis (trimethylsilyl) amide (100mL, 100 mmol) was added dropwise into a solution of 4-picoline (4.6 g,49.4 mmol) and ethyl 2-furancarboxylate (7.7 g, 54.9 mmol) intetrahydrofuran (40 mL) at 0° C. over 1 hour, followed by stirring as itwas for 2 hours. Hexane (140 mL) was added to the reaction solution, andthe resulting crystals were collected by filtration. The resultingcrystals were dissolved in ethyl acetate and an aqueous saturatedsolution of ammonium chloride. The organic layer was washed with anaqueous saturated solution of ammonium chloride (×2) and brine, driedover anhydrous sodium sulfate, and concentrated. Hexane was added to theresidue, and the resulting precipitates were collected by filtration andwashed with hexane, to give the title compound (6.5 g, 70%) as a paleyellow solid.

[0109]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 4.26 (2H, s), 6.77 (1H, dd,J=2.0, 3.6 Hz), 7.31 (2H, dd, J=1.6, 4.4 Hz), 7.65 (1H, dd, J=0.8, 3.6Hz), 8.05 (1H, dd, J=0.8, 2.0 Hz), 8.51 (2H, dd, J=1.6, 4.4 Hz).

Reference Example 2

[0110] 3-(Dimethylamino)-1-(2-furyl)-2-(4-pyridyl)-2-propen-1-one

[0111] N,N-Dimethylformamide dimethylacetal (5 mL) was added to1-(2-furyl)-2-(4-pyridyl)-1-ethanone (2.0 g, 10.7 mmol), followed bystirring at 100° C. for 2 hours. After cooling as it was, the reactionsolution was diluted with ethyl acetate and an aqueous saturatedsolution of ammonium chloride. The aqueous layer was extracted withethyl acetate (×6). The combined organic layer was dried over anhydroussodium sulfate and concentrated, to give the title compound (2.5 g, 97%)as a reddish brown oil.

[0112]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.80 (6H, br s), 6.53 (1H, br),6.60 (1H, br), 7.10 (2H, d, J=4.0 Hz), 7.65 (1H, br), 7.75 (1H, s), 8.44(2H, d, J=4.0 Hz).

Reference Example 3

[0113]6-(2-Furyl)-2-oxo-5-(4-pyridyl)-1,2-dihydro-3-pyridinecarbonitrile

[0114] Sodium methoxide (1.20 g, 22.2 mmol) was added to a solution of3-(dimethylamino)-1-(2-furyl)-2-(4-pyridyl)-2-propen-1-one (2.27 g, 9.37mmol) and2-cyanoacetamide (950 mg, 11.3 mmol) in N,N-dimethylformamide,followed by stirring at 80° C. for 2 hours in a nitrogen atmosphere.After cooling as it was, the reaction solution was concentrated anddiluted with water. After neutralized with 6 N hydrochloric acid, theresulting solid was collected by filtration and washed with water, togive the title compound (1.78 g, 72%) as a pale brown solid.

[0115]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.64 (1H, dd, J=1.6, 4.0 Hz),6.92 (1H, d, J=4.0 Hz), 7.24 (2H, dd, J=1.6, 4.4 Hz), 7.75 (1H, dd,J=0.8, 1.6 Hz), 8.21 (1H, s), 8.57 (2H, dd, J=1.6, 4.4 Hz).

Reference Example 4

[0116] 2-Chloro-6-(2-furyl)-5-(4-pyridyl)-3-pyridinecarbonitrile

[0117] A suspension of6-(2-furyl)-2-oxo-5-(4-pyridyl)-1,2-dihydro-3-pyridinecarbonitrile (21.0g, 79.8 mmol) in phosphorus oxychloride (90 g) was stirred in a nitrogenatmosphere at 110° C. After 4 hours, additional phosphorus oxychloride(50 g) was added thereto, followed by heating under stirring for further5 hours. After cooling as it was, the reaction solution wasconcentrated. After ice was added to the residue, it was neutralizedwith saturated sodium bicarbonate. After extracting with ethyl acetate(2 1) -tetrahydrofuran (1 1), the organic layer was washed with brine,dried over anhydrous magnesium sulfate and concentrated. After addingdiethyl ether to the residue, the resulting solid was collected byfiltration and washed with diethyl ether, to give the title compound(13.6 g, 61%) as a dark yellow solid.

[0118]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.62 (1H, dd, J=1.6, 3.6 Hz),6.78 (1H, dd, J=0.8, 3.6 Hz), 7.42 (2H, dd, J=1.6, 4.4 Hz), 7.76 (1H,dd, J=0.8, 1.6 Hz), 8.48 (1H, s), 8.69 (2H, dd, J=1.6, 4.4 Hz).

Reference Example 5

[0119] 3-(Dimethylamino)-1-(2-furyl)-2-propen-1-one

[0120] A mixture of 2-acetylfuran (25.0 g, 0.227 mmol) andN,N-dimethylformamide dimethylacetal (40 ml) was stirred at 100° C. for9 hours. After cooling as it was, the reaction solution wasconcentrated. Diethyl ether and hexane were added to the residue, andthe resulting solid was collected by filtration and washed with hexane,to give the title compound (36.5 g, 97%) as a brown solid.

[0121]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.88 (3H, br s), 3.14 (3H, br s),5.65 (1H, d, J=12.6 Hz), 6.60 (1H, dd, J=2.0, 3.4 Hz), 7.10 (1H, dd,J=0.8, 3.4 Hz), 7.68 (1H, d, J=12.6 Hz), 7.79 (1H, dd, J=0.8, 2.0 Hz).

Reference Example 6

[0122] 6-(2-Furyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile

[0123] A suspension of 3-(dimethylamino)-1-(2-furyl)-2-propen-1-one(15.0 g, 90.9 mmol), 2-cyanoacetamide (8.5 g, 101 mmol) and potassiumcarbonate (38.0 g, 275 mmol) in dimethyl sulfoxide (80 ml) was stirredat 120 to 140° C. for 21 hours. After cooling as it was, the reactionmixture was diluted with water. After adjusting to pH 3 with conc.hydrochloric acid, the resulting solid was collected by filtration andwashed with water, to give the title compound (13.0 g, 77%) as a brownsolid.

[0124]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.75 (1H, d, J=8.0 Hz), 6.78 (1H,dd, J=1.6, 3.6 Hz), 7.61 (1H, d, J=3.6 Hz), 8.02 (1H, d, J=1.6 Hz), 8.15(1H, d, J=8.0 Hz).

Reference Example 7

[0125] 2-[[3-Cyano-6-(2-furyl)-2-pyridyl]oxy]acetamide

[0126] A suspension of6-(2-furyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (6.0 g, 32.3 mmol),2-chloroacetamide (3.0 g, 37.7 mmol), sodium iodide (5.7 g, 38.0 mmol)and potassium carbonate (9.0 g, 56.2 mmol) in acetone (100 ml) wasstirred at 60° C. for 6 hours. After cooling as it was, the reactionsolution was diluted with ethyl acetate and water. The organic layer waswashed with an aqueous saturated solution of sodium bicarbonate (×2) andan aqueous saturated solution of ammonium chloride, dried over anhydroussodium sulfate, and concentrated. Diethyl ether was added to theresidue, and the resulting precipitates were collected by filtration andwashed with diethyl ether, to give the title compound (4.2 g, 54%) as abrown solid.

[0127]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 4.87 (2H, s), 6.75 (1H, dd,J=2.0, 3.4 Hz), 7.26 (1H, br), 7.26 (1H, dd, J=0.8, 3.4 Hz), 7.45 (1H,d, J=8.0 Hz), 7.61 (1H, br), 7.96 (1H, dd, J=0.8, 2.0 Hz), 8.29 (1H, d,J=8.0 Hz).

Reference Example 8

[0128] 2-Amino-6-(2-furyl)nicotinonitrile

[0129] A suspension of 2-[[3-cyano-6-(2-furyl)-2-pyridyl]oxy]acetamide(8.0 g, 32.9 mmol) and potassium carbonate (9.1 g, 65.9 mmol) inN,N-dimethylformamide (80 ml) was stirred at 120° C. for 1.5 hours.After cooling as it was, the reaction solution was diluted with waterand ethyl acetate, and the insoluble matters were filtered off. Theaqueous layer in the filtrate was extracted with ethyl acetate. Thecombined organic layer was washed with an aqueous saturated solution ofammonium chloride (×2), dried over anhydrous sodium sulfate, andconcentrated. The residue was suspended in methanol, and the resultingsolid was collected by filtration and washed with methanol, to give thetitle compound (3.81 g, 63%) as a brown solid.

[0130]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.68 (1H, dd, J=1.6, 3.6 Hz),6.96 (2H, br s), 7.02 (1H, d, J=8.2 Hz), 7.13 (1H, dd, J=0.8, 3.6 Hz),7.89 (1H, dd, J=0.8, 1.6 Hz), 7.91 (1H, d, J=8.2 Hz).

Reference Example 9

[0131] 2-Amino-5-bromo-6-(2-furyl)nicotinonitrile

[0132] N-Bromosuccinimide (3.5 g, 19.7 mmol) was added to a solution (60ml) of 2-amino-6-(2-furyl)nicotinonitrile (4.0 g, 21.6 mmol) inN,N-dimethylformamide in a nitrogen atmosphere at 1 to 2° C., followedby stirring as it was. After 30 minutes, the reaction solution wasdiluted with ethyl acetate and an aqueous saturated solution ofpotassium carbonate. The organic layer was washed with an aqueoussaturated solution of potassium carbonate and an aqueous saturatedsolution of ammonium chloride, then dried over anhydrous sodium sulfateand concentrated. Methanol was added to the residue, and the resultingsolid was collected by filtration and washed with methanol, to give thetitle compound (3.02 g, 53%) as a brown solid.

[0133]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.72 (1H, dd, J=1.8, 3.6 Hz),7.19 (2H, br s), 7.44 (1H, dd, J=0.8, 3.6 Hz), 7.96 (1H, dd, J=0.8, 1.8Hz), 8.26 (1H, s)

Reference Example 10

[0134] 5-Bromo-2-methoxypyridine

[0135] After sodium (10 g, 0.435 mol) was dissolved in methanol (500ml), 2,5-dibromopyridine (50 g, 0.211 mol) was added thereto and themixture was heated for 2 days under reflux. The reaction solution wascooled as it was, and then concentrated. Then, the residue was dilutedwith ethyl acetate and an aqueous saturated solution of ammoniumchloride. The organic layer was washed with an aqueous saturatedsolution of ammonium chloride and brine, and then dried over anhydroussodium sulfate and concentrated, to give the title compound (33 g, 83%)as a pale brown oil.

[0136]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.84 (3H, s), 6.72 (1H, dd,J=0.8, 8.8 Hz), 7.89 (1H, dd, J=2.4, 8.8 Hz), 8.29 (1H, dd, J=0.8, 2.4Hz).

Reference Example 11

[0137] 2-Methoxy-5-(1,1,1-tributylstannyl)pyridine

[0138] 2.5 M n-butyl lithium solution in hexane (12.0 ml, 30.0 mmol) wasadded dropwise to a solution of 5-bromo-2-methoxypyridine (5.0 g, 26.6mmol) in tetrahydrofuran (100 ml) over 30 minutes at −70° C. in anitrogen atmosphere. Then, a solution of tributyltin chloride (10.4 ml,32.0 mmol) in tetrahydrofuran (20 ml) was added dropwise thereinto over1 hour. Then, the reaction solution was heated to room temperature andstirred as it was. After 30 minutes, the reaction solution was dilutedwith an aqueous saturated solution of ammonium chloride and ethylacetate. The organic layer was washed with an aqueous saturated solutionof ammonium chloride and brine, dried over anhydrous sodium sulfate andconcentrated. The residue was subjected to silica gel columnchromatography (elution solvent; hexane, hexane:ethyl acetate=40:1), togive the title compound (7.9 g, 75%) as a colorless oil.

[0139]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 0.82-0.90 (9H, m), 1.02-1.08 (6H,m), 1.22-1.35 (6H, m), 1.46-1.54 (6H, m), 3.82 (3H, s), 6.80 (1H, dd,J=0.8, 8.0 Hz), 7.69 (1H, dd, J=1.6, 8.0 Hz), 8.10 (1H, dd, J=0.8, 1.6Hz).

Reference Example 12

[0140] (E)-1,3-Di(3-fluorophenyl)-2-propen-1-one

[0141] A mixture of 3-fluorobenzaldehyde (7.63 mL, 72.4 mmol),3-fluoroacetophenone (10 g, 72.4 mmol), potassium hydroxide (5.18 g,92.6 mmol), ethanol (23 mL) and water (47 mL) was stirred overnight atroom temperature. After the reaction solution was diluted with water,the solid was collected by filtration and washed with ethanol anddiethyl ether, to give the title compound (16.4 g, 93%).

[0142]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 7.10-7.16 (1H, m), 7.27-7.37 (2H,m), 7.39-7.42 (2H, m), 7.46 (1H, d, J=15 Hz), 7.50 (1H, dd, J=5.4, 7.7Hz), 7.68-7.73 (1H, m), 7.77 (1H, d, J=15 Hz), 7.78-7.82 (1H, m).

Reference Example 13

[0143] 4,6-Di(3-fluorophenyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile

[0144] (E)-1,3-Di(3-fluorophenyl)-2-propen-1-one (16.4 g, 67.2 mmol),2-cyanoacetamide (6.21 g, 73.9 mmol), and a solution of potassiumt-butoxide (30.2 g, 269 mmol) in dimethyl sulfoxide (131 mL) werestirred overnight at room temperature in an oxygen atmosphere. Water(300 mL) and 6 N hydrochloric acid (390 mL) were added to the reactionsolution. The solid was collected by filtration and washed with water,to give the title compound (17.4 g, 84%).

[0145]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.81 (1H, s), 7.28-7.36 (1H, m),7.50-7.58 (1H, m), 7.68-7.88 (2H, m).

Reference Example 14

[0146] Isopropyl 3-(2-furyl)-3-oxopropanethioate

[0147] A mixture of isopropyl (methylsulfanyl)methanethioate (7.0 g,46.7 mmol), 2-acetyl furan (5.14 g, 46.7 mmol), potassium t-butoxide(10.5 g, 93.5 mmol) and t-butanol (35 mL) was stirred overnight at roomtemperature. Ice was added to the reaction solution, followed byacidifying with 5 N hydrochloric acid. The solid was collected byfiltration and washed with water, to give the title compound (3.7 g,37%).

[0148]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.38 (6H, d, J=8.8 Hz), 5.58-5.69(1H, m), 6.27 (1H, s), 6.53 (1H, dd, J=2.0, 3.3 Hz), 7.05 (1H, dd,J=0.4, 3.3 Hz), 7.52 (1H, dd, J=0.4, 2.0 Hz).

Reference Example 15

[0149] (Z)-1-(2-Furyl)-3-isopropoxy-3-(methylsulfanyl)-2-propen-1-one

[0150] A mixture of isopropyl 3-(2-furyl)-3-oxopropanethioate (3.7 g,17.5 mmol), potassium carbonate (7.3 g, 52.4 mmol) and acetone (15 mL)was heated under reflux for 1 hour. After cooling the mixture to 0° C.,methyl iodide (2.17 mL, 34.9 mmol) was added thereto, followed bystirring at room temperature for 2 hours. After diluting the reactionsolution with ethyl acetate, the insoluble matters were filtered off.The filtrate was concentrated, and then the residue was purified bysilica gel column chromatography (elution solvent; ethylacetate/hexane=1:1), to give the title compound (3.2 g, 81%).

[0151]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.42 (6H, d, J=6.0 Hz), 2.28 (3H,s), 4.72-4.82 (1H, m), 6.35 (1H, s), 6.49 (1H, dd, J=1.5, 3.6 Hz), 7.10(1H, dd, J=1.0, 3.6 Hz), 7.47 (1H, dd, J=1.0, 1.5 Hz).

Reference Example 16

[0152] 6-(2-Furyl)-4-isopropoxy-2-oxo-1,2-dihydro-3-pyridinecarbonitrile

[0153] Sodium (309 mg, 13.4 mmol) was dissolved in isopropanol (46 mL).Then, (Z)-1-(2-furyl)-3-isopropoxy-3-(methylsulfanyl)-2-propen-1-one(3.03 g, 13.4 mmol) and 2-cyanoacetamide (1.13 g, 13.4 mmol) were addedthereto, followed by stirring overnight at room temperature. Ice-waterwas added to the reaction solution, and then the solid was collected byfiltration, and washed with water and diethyl ether, to give the titlecompound (2.3 g, 70%).

[0154]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.35 (6H, d, J=6.0 Hz), 4.98-5.08(1H, m), 6.60-6.66 (1H, m), 6.77-6.81 (1H, m), 7.60-7.67 (1H, m),8.00-8.05 (1H, m).

Example 1

[0155] 2-Amino-6-(2-furyl)-5-(4-pyridyl)-3-pyridinecarbonitrile

[0156] A solution of ammonia in ethanol, 30 ml, (ethanol saturated at 0°C. with an ammonia gas) was added to2-chloro-6-(2-furyl)-5-(4-pyridyl)-3-pyridinecarbonitrile (200 mg, 0.710mmol). Then, it was sealed in a stainless steel autoclave, and heatedunder stirring at 100° C. After 24 hours, the reaction solution wascooled as it was and concentrated. The residue was subjected to silicagel column chromatography (elution solvent; hexane, hexane:ethylacetate=2:1, 1:1, 1:2), and then suspended in diethyl ether. Theresulting precipitates were collected by filtration and washed withdiethyl ether, to give the title compound (50 mg, 27%) as a pale orangesolid.

[0157]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.54 (1H, dd, J=1.6, 3.6 Hz),6.57 (1H, dd, J=0.8, 3.6 Hz), 7.20 (2H, br s), 7.24 (2H, dd, J=1.6, 4.4Hz), 7.64 (1H, dd, J=0.8, 1.6 Hz), 7.92 (1H, s), 8.55 (2H, dd, J=1.6,4.4 Hz);

[0158] MS m/e (ESI) 263 (MH⁺).

Example 2

[0159] 2-Amino-6-(fluorophenyl)-5-(4-pyridyl)-3-pyridinecarbonitrile

[0160] The title compound was synthesized in the same manner as inExamples 18 to 20 described below or by its analogous method.

[0161]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.99-7.03 (1H, m), 7.09-7.14 (3H,m), 7.16-7.22 (1H, m), 7.28-7.35 (3H, m), 8.09 (1H, s), 8.43 (2H, dd,J=1.6, 4.4 Hz);

[0162] MS m/e (ESI) 291 (MH⁺).

Example 3

[0163]2-Amino-6-(2-furyl)-5-(4-methoxy-3-pyridyl)-3-pyridinecarbonitrile

[0164] A solution of 2-amino-5-bromo-6-(2-furyl)nicotinonitrile (1.80 g,6.82 mmol), 2-methoxy-5-(1,1,1-tributylstannyl)pyridine (5.20 g, 13.1mmol) and dichlorobis(triphenylphosphine) palladium (II) (480 mg, 0.634mmol) in N,N-dimethylformamide (18 ml) was stirred at 80° C. for 2 hoursin a nitrogen atmosphere. After cooling as it was, the reaction solutionwas diluted with ethyl acetate and an aqueous saturated solution ofammonium chloride. The organic layer was washed with an aqueoussaturated solution of ammonium chloride (×2), then dried over anhydroussodium sulfate and concentrated. The residue was subjected to silica gelcolumn chromatography (elution solvent; hexane, hexane:ethylacetate=8:1, 4:1), and then suspended in diethyl ether. The resultingsolid was collected by filtration and washed with diethyl ether, to givethe title compound (1.12 g, 56%) as a yellow solid.

[0165]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.88 (3H, s), 6.38 (1H, dd,J=0.8, 3.6 Hz), 6.51 (1H, dd, J=1.6, 3.6 Hz), 6.83 (1H, d, J=4.6 Hz),7.08 (2H, br s), 7.54 (1H, dd, J=2.4, 4.6 Hz), 7.67 (1H, dd, J=0.8, 1.6Hz), 7.84 (1H, s), 8.04 (1H, d, J=2.4 Hz).

Example 4

[0166]2-Amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile

[0167] A solution of2-amino-6-(2-furyl)-5-(4-methoxy-3-pyridyl)-3-pyridinecarbonitrile (1.0g, 3.42 mmol) in acetic acid (6 ml) -conc. hydrobromic acid (10 ml) wasstirred at 100° C. for 1.5 hours. After cooling as it was, the reactionsolution was adjusted to pH 12 to 13 with 5 N sodium hydroxide andwashed with ethyl acetate. The organic layer was extracted with 1 Nsodium hydroxide (×2), and then the combined aqueous layer wasneutralized with 5 N hydrochloric acid. The resulting solid wascollected by filtration, to give the title compound (760 mg) as yellowcrude crystals. After suspending the product in methanol, 4 N HCl/ethylacetate was added thereto to dissolved and it subjected to silica gelcolumn chromatography (elution solvent; dichloromethane,dichloromethane:methanol=40:1, 20:1, 10:1). The resulting crudeobjective compound was suspended in water, and then neutralized with 5 Nsodium hydroxide. The solid was collected by filtration and washed withwater, to give the title compound (486 mg, 51%) as a yellow solid.

[0168]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.30 (1H, d, J=9.6 Hz), 6.57 (1H,dd, J=1.8, 3.4 Hz), 6.59 (1H, dd, J=0.6, 3.4 Hz), 7.02 (2H, br s), 7.20(1H, dd, J=2.8, 9.6 Hz), 7.33 (1H, d, J=2.8 Hz), 7.75 (1H, dd, J=0.6,1.8 Hz), 7.82 (1H, s); MS m/e (ESI) 279 (MH⁺).

Example 5

[0169]2-Amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinonitrile

[0170] Sodium methoxide (155 mg, 2.87 mmol) was added to a suspension of2-amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile(400 mg, 1.44 mmol) in methanol (8 ml) at room temperature in a nitrogenatmosphere, followed by stirring. After 15 minutes, iodoethane (0.35 ml,4.38 mmol) was added thereto, followed by stirring as it was. After 15hours, additional iodoethane (0.35 ml, 4.38 mmol) was added thereto, andthe mixture was further stirred. After 24 hours, the reaction solutionwas concentrated. The residue was subjected to silica gel columnchromatography (elution solvent; hexane, hexane:ethyl acetate=2:1, 1:2,1:5). The resulting crude objective compound was suspended in diethylether, and then the solid was collected by filtration and washed withdiethyl ether, to give the title compound (149 mg, 34%) as a pale yellowsolid.

[0171]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.23 (3H, t, J=7.2 Hz), 3.91 (2H,q, J=7.2 Hz), 6.34 (1H, d, J=9.2 Hz), 6.57 (1H, dd, J=2.0, 3.2 Hz), 6.62(1H, dd, J=0.8, 3.2 Hz), 7.06 (2H, br s), 7.19 (1H, dd, J=2.8, 9.2 Hz),7.71 (1H, d, J=2.8 Hz), 7.75 (1H, dd, J=0.8, 2.0 Hz), 7.88 (1H, s); MSm/e (ESI) 307 (MH⁺).

Example 6

[0172]2-Amino-6-(2-furyl)-5-(1-methyl-6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile

[0173] The title compound was synthesized in the same manner as inExample 30.

[0174]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.45 (3H, s), 6.35 (1H, d, J=9.2Hz), 6.57 (1H, dd, J=1.6, 3.6 Hz), 6.65 (1H, dd, J=0.8, 3.6 Hz), 7.06(2H, br s), 7.17 (1H, dd, J=2.8, 9.2 Hz), 7.75 (1H, d, J=2.8 Hz), 7.76(1H, dd, J=0.8, 1.6 Hz), 7.84 (1H, s); MS m/e (ESI) 293 (MH⁺).

Example 7

[0175]2-Amino-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile

[0176] The title compound was synthesized in the same manner as inExamples 21 to 29.

[0177]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.19 (1H, d, J=9.6 Hz), 6.86 (2H,br s), 7.00 (1H, dd, J=2.8, 9.6 Hz), 7.17-7.28 (4H, m), 7.37-7.45 (1H,m), 8.26 (1H, s) MS m/e (ESI) 307 (MH⁺).

Example 8

[0178]2-Amino-6-(3-fluorophenyl)-5-(1-methyl-6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile

[0179] Using2-amino-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile,the title compound was synthesized in the same manner as in Example 30.

[0180]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.40 (3H, s), 6.17 (1H, d, J=9.6Hz), 6.85 (1H, dd, J=2.4, 9.6 Hz), 7.12 (2H, br s), 7.14-7.26 (3H, m),7.34-7.42 (1H, m), 7.74 (1H, d, J=2.4 Hz), 7.98 (1H, s); MS m/e (ESI)321 (MH⁺).

Example 9

[0181] 2-Amino-5-(4-cyanophenyl)-6-(2-furyl)nicotinonitrile

[0182] 2-Amino-5-bromo-6-(2-furyl)nicotinonitrile (20 mg, 75.7 μmol),4-cyanophenylboric acid (30 mg, 204 μmol), dichlorobis(acetonitrile)palladium (II) (2 mg, 7.71 μmol), and a solution of 2 M aqueouspotassium carbonate (150 μL, 300 μmol) in N,N-dimethylformamide (0.6 mL)was stirred at 80° C. for 14 hours. After cooling as it was, thereaction solution was diluted with ethyl acetate and water. Afterfiltering off the insoluble matters, the organic layer in the filtratewas concentrated. A half of the residue was purified by HPLC on areverse phase column and using a water-acetonitriletrifluoroacetic acidsystem as the elution solvent, to give the title compound (3.33 mg). MSm/e (ESI) 401 (MH⁺).

[0183] The title compounds of the following Examples 10 to 76 weresynthesized in the same manner as in Example 3 or 9, or by its analogousmethod.

Example 10

[0184] 2-Amino-5,6-di(2-furyl)nicotinonitrile

Example 11

[0185] 2-Amino-5-(4-cyanophenyl)-6-(2-furyl)nicotinonitrile

Example 12

[0186] 2-Amino-6-(2-furyl)-5-phenylnicotinonitrile

Example 13

[0187] 2-Amino-6-(2-furyl)-5-(4-methylphenyl)nicotinonitrile

Example 14

[0188] 2-Amino-6-(2-furyl)-5-(3-methylphenyl)nicotinonitrile

Example 15

[0189] 2-Amino-6-(2-furyl)-5-(2-methylphenyl)nicotinonitrile

Example 16

[0190] 2-Amino-6-(2-furyl)-5-(4-methoxyphenyl)nicotinonitrile

Example 17

[0191] 2-Amino-6-(2-furyl)-5-(3-methoxyphenyl)nicotinonitrile

Example 18

[0192] 2-Amino-5-(2,4-dimethoxyphenyl)-6-(2-furyl)nicotinonitrile

Example 19

[0193] 2-Amino-5-(3,4-dimethoxyphenyl)-6-(2-furyl)nicotinonitrile

Example 20

[0194] 2-Amino-6-(2-furyl)-5-(3,4,5-trimethoxyphenyl)nicotinonitrile

Example 21

[0195] 2-Amino-5-(1,3-benzodioxol-5-yl)-6-(2-furyl)nicotinonitrile

Example 22

[0196] 2-Amino-5-[4-(benzyloxy)phenyl]-6-(2-furyl)nicotinonitrile

Example 23

[0197] 2-Amino-5-[3-(benzyloxy)phenyl]-6-(2-furyl)nicotinonitrile

Example 24

[0198] 2-Amino-6-(2-furyl)-5-(4-phenoxyphenyl)nicotinonitrile

Example 25

[0199] 2-Amino-5-(3-ethoxyphenyl)-6-(2-furyl)nicotinonitrile

Example 26

[0200] 2-Amino-6-(2-furyl)-5-[4-(trifluoromethoxy)phenyl]nicotinonitrile

Example 27

[0201]2-Amino-6-(2-furyl)-5-[3-(trifluoromethoxy)phenyl)nicotinonitrile]

Example 28

[0202] 2-Amino-5-(4-dimethylaminophenyl)-6-(2-furyl)nicotinonitrile

Example 29

[0203] 2-Amino-6-(2-furyl)-5-[4-(methylsulfanyl)phenyl]nicotinonitrile

Example 30

[0204] 2-Amino-5-(4-fluorophenyl)-6-(2-furyl)nicotinonitrile

Example 31

[0205] 2-Amino-5-(3-fluorophenyl)-6-(2-furyl)nicotinonitrile

Example 32

[0206] 2-Amino-5-(2-fluorophenyl)-6-(2-furyl)nicotinonitrile

Example 33

[0207] 2-Amino-5-(2,4-difluorophenyl)-6-(2-furyl)nicotinonitrile

Example 34

[0208]2-Amino-6-(2-furyl)-5-(2,3,4,5,6-pentafluorophenyl)nicotinonitrile

Example 35

[0209] 2-Amino-6-(2-furyl)-5-[4-(trifluoromethyl)phenyl]nicotinonitrile

Example 36

[0210] 2-Amino-6-(2-furyl)-5-[3-(trifluoromethyl)phenyl]nicotinonitrile

Example 37

[0211] 2-Amino-6-(2-furyl)-5-[2-(trifluoromethyl)phenyl]nicotinonitrile

Example 38

[0212]2-Amino-5-[3,5-di(trifluoromethyl)phenyl]-6-(2-furyl)nicotinonitrile

Example 39

[0213] 2-Amino-6-(2-furyl)-5-(4-nitrophenyl)nicotinonitrile

Example 40

[0214] 2-Amino-6-(2-furyl)-5-(3-nitrophenyl)nicotinonitrile

Example 41

[0215] 2-Amino-6-(2-furyl)-5-(4-methyl-3-nitrophenyl)nicotinonitrile

Example 42

[0216] 2-Amino-5-(2-fluoro-4-biphenylyl)-6-(2-furyl)nicotinonitrile

Example 43

[0217] 2-Amino-6-(2-furyl)-5-(4-methylsulfonylphenyl)nicotinonitrile

Example 44

[0218] 2-Amino-6-(2-furyl)-5-(4-methylsulfinylphenyl)nicotinonitrile

Example 45

[0219] 2-Amino-5-(4-biphenylyl)-6-(2-furyl)nicotinonitrile

Example 46

[0220] 2-Amino-5-(3-biphenylyl)-6-(2-furyl)nicotinonitrile

Example 47

[0221] 2-Amino-5-(3-cyanophenyl)-6-(2-furyl)nicotinonitrile

Example 48

[0222] 5-(4-Acetylphenyl)-2-amino-6-(2-furyl)nicotinonitrile

Example 49

[0223] 5-(3-Acetylphenyl)-2-amino-6-(2-furyl)nicotinonitrile

Example 50

[0224] 5-(2-Acetylphenyl)-2-amino-6-(2-furyl)nicotinonitrile

Example 51

[0225] 2-Amino-5-(3-formylphenyl)-6-(2-furyl)nicotinonitrile

Example 52

[0226] 2-Amino-5-(2-formylphenyl)-6-(2-furyl)nicotinonitrile

Example 53

[0227] 2-Amino-5-(3-chlorophenyl)-6-(2-furyl)nicotinonitrile

Example 54

[0228] 2-Amino-5-(2-chlorophenyl)-6-(2-furyl)nicotinonitrile

Example 55

[0229] 2-Amino-5-(2,4-dichlorophenyl)-6-(2-furyl)nicotinonitrile

Example 56

[0230] 2-Amino-5-(3,4-dichlorophenyl)-6-(2-furyl)nicotinonitrile

Example 57

[0231] 2-Amino-5-(2,5-dichlorophenyl)-6-(2-furyl)nicotinonitrile

Example 58

[0232] 2-Amino-5-(4-tert-butylphenyl)-6-(2-furyl)nicotinonitrile

Example 59

[0233] 2-Amino-6-(2-furyl)-5-(1-naphthyl)nicotinonitrile

Example 60

[0234] 2-Amino-6-(2-furyl)-5-(2-naphthyl)nicotinonitrile

Example 61

[0235] 2-Amino-5-benzo[b]furan-2-yl-6-(2-furyl)nicotinonitrile

Example 62

[0236] 2-Amino-5-dibenzo[b,d]furan-4-yl-6-(2-furyl)nicotinonitrile

Example 63

[0237] 2-Amino-6-(2-furyl)-5-(3-furyl)nicotinonitrile

Example 64

[0238] 2-Amino-6-(2-furyl)-5-(2-thienyl)nicotinonitrile

Example 65

[0239] 2-Amino-6-(2-furyl)-5-(3-thienyl)nicotinonitrile

Example 66

[0240] 2-Amino-6-(2-furyl)-5-(5-methyl-2-thienyl)nicotinonitrile

Example 67

[0241] 2-Amino-6-(2-furyl)-5-(4-methyl-2-thienyl)nicotinonitrile

Example 68

[0242] 5-(5-Acetyl-2-thienyl)-2-amino-6-(2-furyl)nicotinonitrile

Example 69

[0243] 2-Amino-5-(2-formyl-3-thienyl)-6-(2-furyl)nicotinonitrile

Example 70

[0244] 2-Amino-5-(3-formyl-2-thienyl)-6-(2-furyl)nicotinonitrile

Example 71

[0245] 2-Amino-5-(5-chloro-2-thienyl)-6-(2-furyl)nicotinonitrile

Example 72

[0246] 2-Amino-5-benzo[b]thiophen-2-yl-6-(2-furyl)nicotinonitrile

Example 73

[0247] 2-Amino-5-benzo[b]thiophen-3-yl-6-(2-furyl)nicotinonitrile

Example 74

[0248] 2-Amino-6-(2-furyl)-5-(3-pyridyl)nicotinonitrile

Example 75

[0249] 2-Amino-6-(2-furyl)-5-(2-pyridyl)nicotinonitrile

Example 76

[0250] 2-Amino-6-(2-furyl)-5-(4-vinylphenyl)nicotinonitrile

Example 77

[0251]2-Amino-5-(l-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinicacid

[0252] Ethanol (5 mL) and 5 N aqueous sodium hydroxide (10 mL) wereadded to2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinonitrile(308 mg, 1.01 mmol), followed by heating under reflux for 4 hours. Aftercooling as it was, the reaction solution was neutralized with 5 Nhydrochloric acid. The resulting solid was collected by filtration andthen washed with water, to give the title compound (320 mg, 98%) as ayellow solid.

[0253]¹H-NMR (400 MHz, DMSO-d₆) δ ppm; 1.22 (3H, t, J=7.2 Hz), 3.92 (2H,q, J=7.2 Hz), 6.35 (1H, d, J=9.2 Hz), 6.54-6.58 (1H, m), 6.60 (1H, dd,J=0.8, 3.6 Hz), 7.21 (1H, dd, J=2.4, 9.2 Hz), 7.31 (2H, br), 7.71 (1H,d, J=2.4 Hz), 7.73 (1H, dd, J=0.8, 3.6 Hz), 7.93 (1H, s);

[0254] The title compounds of the following Examples 78 and 79 weresynthesized in the same manner as in the above-mentioned Example 77 orby its analogous method.

Example 78

[0255] 2-Amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinicacid

Example 79

[0256] 2-Amino-6-(3-fluorophenyl)-5-(4-pyridyl)nicotinonitrile

Example 80

[0257]2-Amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

[0258]2-Amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinicacid (20 mg, 61.5 μmol), 1-hydroxybenzotriazole (28 mg, 183 μmol),3-(3′-dimethylaminopropyl)-1-ethyl carbodiimide (29 mg, 187 μmol),ammonium chloride (16 mg, 299 μmol), and a suspension of triethylamine(43 μL, 309 μmol) in N,N-dimethylformamide (1.0 mL) was stirred at roomtemperature for 18 hours. After diluting the reaction solution withwater, the resulting solid was collected by filtration and washed withwater, to give the title compound (9 mg, 45%) as a pale yellow solid.

[0259]¹H-NMR (400 MHz, DMSO-d₆) δ ppm; 1.24 (3H, t, J=7.2 Hz), 3.92 (2H,q, J=7.2 Hz), 6.37 (1H, d, J=9.2 Hz), 6.53-6.56 (1H, m), 6.58 (1H, dd,J=0.8, 3.2 Hz), 7.23 (1H, dd, J=2.8, 9.2 Hz), 7.37 (3H, br), 7.67 (1H,d, J=2.8 Hz), 7.70 (1H, dd, J=0.8, 3.2 Hz), 7.93 (1H, s), 7.99 (1H, br);

[0260] The title compounds of the following Examples 81 to 102 wereobtained in the same manner as in the above-mentioned Example 80 or byits analogous method.

Example 81

[0261] 2-Amino-6-(3-fluorophenyl)-5-(4-pyridyl)nicotinamide

Example 82

[0262]N-(2-Hydroxyethyl)-2-amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinamide

Example 83

[0263]N-Cyclopropyl-2-amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinamide

Example 84

[0264]N,N-Dimethyl-2-amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinamide

Example 85

[0265]N-Cyclopropylmethyl-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 86

[0266]N-(2-Fluoroethyl)-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 87

[0267]N-Cyclopropyl-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 88

[0268]N-(3-Diethylamino)propyl-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 89

[0269]N-Methyl-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 90

[0270]N-Phenyl-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 91

[0271]N-Allyl-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 92

[0272]N-(2-Amino-2-oxoethyl)-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 93

[0273]N-Isobutyl-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 94

[0274]N-(5-Cyanopentyl)-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 95

[0275]N-[3-(2-Oxotetrahydro-1H-1-pyrrolyl)propyl]-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 96

[0276]N-(2-Pyridylmethyl)-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 97

[0277]N-(3-Pyridylmethyl)-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 98

[0278]N-[2-(4-Pyridyl)ethyl]-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 99

[0279]N-[2-(2-Pyridyl)ethyl]-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 100

[0280]N-(2-Propynyl)-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 101

[0281]N-(3-Hydroxypropyl)-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 102

[0282]N-Ethyl-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinamide

Example 103

[0283] 103-(a):

[0284]2-Amino-6-(2-furyl)-5-(6-oxo-1-propyl-1,6-dihydro-3-pyridinyl)nicotinonitrile

[0285] 103-(b)

[0286] 2-Amino-6-(2-furyl)-5-(4-propyl-3-pyridyl)-3-pyridinecarbonitrile

[0287]2-Amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile (20mg, 0.072 mmol) and potassium carbonate (30 mg, 0.22 mmol) wereintroduced into a reaction vessel, dissolved in N,N-dimethylformamide (1mL). Propyl iodide (52 mg, 0.31 mmol) was added thereto, followed bystirring at 70° C. for 18 hours. After the reaction was finished, waterwas added thereto, and it was extracted with ethyl acetate. Afterremoving the aqueous layer, the organic layer was concentrated andpurified by high performance liquid chromatography, to give the titleproduct as a yellow solid (2.6 mg, 11%; 1.8 mg, 7.8%).

[0288] 103-(a):

[0289]2-Amino-6-(2-furyl)-5-(6-oxo-1-propyl-1,6-dihydro-3-pyridinyl)nicotinonitrile

[0290]¹H-NMR (400 MHz, CDCl₃) δ ppm; 0.98 (3H, t, J=7.4 Hz), 1.83 (2H,q, J=7.4 Hz), 3.99 (2H, t, J=7.4 Hz), 5.50 (2H, brs), 6.47 (1H, dd,J=3.6, 1.8 Hz), 6.73 (1H, dd, J=3.6, 0.8 Hz), 6.81 (1H, d, J=9.2 Hz),7.26 (1H, m), 7.30 (1H, dd, J=9.2, 2.4 Hz), 7.46 (1H, dd, J=1.8, 0.8Hz), 7.58 (1H, s);

[0291] MS (ESI) m/e 321 (MH⁺).

[0292] 103-(b):

[0293] 2-Amino-6-(2-furyl)-5-(4-propyl-3-pyridyl)-3-pyridinecarbonitrile

[0294]¹H-NMR (400 MHz, CDCl₃) δ ppm; 1.07 (3H, t, J=7.4 Hz), 1.85 (2H,m), 4.30 (2H, t, J=6.6 Hz), 6.38-6.41 (2H, m), 6.81 (1H, dd, J=8.8, 0.8Hz), 7.46-7.48 (2H, m), 7.62 (1H, s), 8.06 (1H, d, J=0.8 Hz)

[0295] MS (ESI) m/e 321 (MH⁺).

Example 104

[0296]2-Amino-5-[1-(4-cyanophenyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinonitrile

[0297]2-Amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile (20mg, 0.071 mmol), 4-cyanophenylboronic acid (35 mg, 0.24 mmol), copperacetate monohydrate (3.0 mg, 0.015 mmol), pyridine (0.015 mL, 0.19 mmol)and N,N-dimethylformamide (1.0 mL) were introduced into a reactionvessel and stirred at room temperature for 20 hours. Water was added tothe reaction solution, followed by extracting with ethyl acetate. Theorganic layer was dried, and then dissolved in dimethyl sulfoxide (1.0mL) and purified by high performance liquid chromatography, to give thetitle compound as a yellow solid (8.32 mg, 62%).

[0298]¹H-NMR (400 MHz, DMSO-d₆) δ ppm: 6.49 (1H, d, J=9.6 Hz), 6.61 (1H,dd, J=1.6, 3.2 Hz), 6.79 (1H, d, J=3.2 Hz), 7.07 (2H, brs), 7.30 (1H,dd, J=2.6, 9.6 Hz), 7.74 (1H, d, J=2.6 Hz), 7.76 (2H, d, J=8.6 Hz), 7.82(1H, d, J=1.6 Hz), 7.98 (1H, s), 8.02 (2H, d, J=8.6 Hz);

[0299] MS (ESI) m/e 380 (MH⁺).

[0300] The title compounds of the following Examples 105 to 146 wereobtained in the same manner as in the above-mentioned Example 5, 103 or104, or by its analogous methods.

Example 105

[0301]2-Amino-6-(2-furyl)-5-[6-oxo-1-(3-phenylpropyl)-1,6-dihydro-3-pyridinyl]nicotinonitrile

Example 106

[0302] Ethyl4-5-[6-amino-5-cyano-2-(2-furyl)-3-pyridyl]-2-oxo-1,2-dihydro-1-pyridinylbutanoate

Example 107

[0303]2-Amino-5-[1-(3-cyanopropyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinonitrile

Example 108

[0304]2-Amino-5-[1-(3-cyanobutylpropyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinonitrile

Example 109

[0305]2-Amino-6-(2-furyl)-5-[6-oxo-1-(4,4,4-trifluorobutyl)-1,6-dihydro-3-pyridinyl]nicotinonitrile

Example 110

[0306]2-Amino-6-(2-furyl)-5-[6-oxo-1-(3,4,4-trifluoro-3-butenyl)-1,6-dihydro-3-pyridinyl]nicotinonitrile

Example 111

[0307]2-Amino-6-(2-furyl)-5-[6-oxo-1-(3,3,3-trifluoropropyl)-1,6-dihydro-3-pyridinyl]nicotinonitrile

Example 112

[0308]2-Amino-5-(1-butyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinonitrile

Example 113

[0309]2-Amino-6-(2-furyl)-5-(1-heptyl-6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile

Example 114

[0310]2-Amino-6-(2-furyl)-5-(1-isopentyl-6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile

Example 115

[0311]5-(1-Allyl-6-oxo-1,6-dihydro-3-pyridinyl)-2-amino-6-(2-furyl)nicotinonitrile

Example 116

[0312]2-Amino-5-[1-(3-butenyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinonitrile

Example 117

[0313]2-Amino-6-(2-furyl)-5-[6-oxo-1-(4-pentenyl)-1,6-dihydro-3-pyridinyl]nicotinonitrile

Example 118

[0314]2-Amino-6-(2-furyl)-5-[1-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinyl]nicotinonitrile

Example 119

[0315]2-Amino-5-[1-(2,3-dihydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinonitrile

Example 120

[0316]2-Amino-5-[1-(3-fluoropropyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinonitrile

Example 121

[0317]2-Amino-5-[1-(3-chloropropyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinonitrile

Example 122

[0318]2-Amino-5-[1-(4-chlorobutyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinonitrile

Example 123

[0319]2-Amino-5-[1-(5-chloropentyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinonitrile

Example 124

[0320]2-Amino-5-[1-(cyclohexylmethyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinonitrile

Example 125

[0321]2-Amino-6-(2-furyl)-5-[6-oxo-1-(tetrahydro-2H-2-pyranylmethyl)-1,6-dihydro-3-pyridinyl]nicotinonitrile

Example 126

[0322]2-Amino-5-(1-benzyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinonitrile

Example 127

[0323]2-Amino-5-[1-(2-cyanoethyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinonitrile

Example 128

[0324]2-Amino-6-(2-furyl)-5-[6-oxo-1-(2-propynyl)-1,6-dihydro-3-pyridinyl]nicotinonitrile

Example 129

[0325]2-Amino-5-[1-(2-butynyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinonitrile

Example 130

[0326]2-Amino-6-(2-furyl)-5-{6-oxo-1-[3-(1,1,1-trimethylsilyl)-2-propynyl]-1,6-dihydro-3-pyridinyl}nicotinonitrile

Example 131

[0327]2-Amino-5-{1-[(6,7-dimethoxy-2-oxo-2H-4-chromenyl)methyl]-6-oxo-1,6-dihydro-3-pyridinyl}nicotinonitrile

Example 132

[0328]2-Amino-5-{1-[4-(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)butyl]-6-oxo-1,6-dihydro-3-pyridinyl}-6-(2-furyl)nicotinonitrile

Example 133

[0329]2-Amino-6-(2-furyl)-5-1-[2-(1H-3-indolyl)ethyl]-6-oxo-{1,6-dihydro-3-pyridinyl}nicotinonitrile

Example 134

[0330]2-Amino-6-(2-furyl)-5-[6-oxo-1-(2-oxopropyl)-1,6-dihydro-3-pyridinyl]nicotinonitrile

Example 135

[0331]2-Amino-6-(2-furyl)-5-{6-oxo-1-2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl-1,6-dihydro-3-pyridinyl}nicotinonitrile

Example 136

[0332]2-Amino-6-(2-furyl)-5-(6-oxo-1-phenyl-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinonitrile

Example 137

[0333]2-Amino-5-[1-(4-cyanophenyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinonitrile

Example 138

[0334]2-Amino-6-(2-furyl)-5-[6-oxo-1-(4-vinylphenyl)-1,6-dihydro-3-pyridinyl]nicotinonitrile

Example 139

[0335]2-Amino-6-(2-furyl)-5-[1-(4-methylphenyl)-6-oxo-1,6-dihydro-3-pyridinyl]nicotinonitrile

Example 140

[0336]2-Amino-6-(2-furyl)-5-[1-(2-methylphenyl)-]6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile

Example 141

[0337]2-Amino-6-(2-furyl)-5-[1-(4-methoxyphenyl)-6-oxo-1,6-dihydro-3-pyridinyl]nicotinonitrile

Example 142

[0338]2-Amino-6-(2-furyl)-5-[1-(3-methoxyphenyl)-6-oxo-1,6-dihydro-3-pyridinyl]nicotinonitrile

Example 143

[0339]2-Amino-6-(2-furyl)-5-[1-(2-methoxyphenyl)-6-oxo-1,6-dihydro-3-pyridinyl]nicotinonitrile

Example 144

[0340]2-Amino-5-[1-(4-fluorophenyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinonitrile

Example 145

[0341]2-Amino-5-[1-(3-fluorophenyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinonitrile

Example 146

[0342]2-Amino-5-[1-(2-fluorophenyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(2-furyl)nicotinonitrile

[0343] The title compounds of the following Examples 147 to 175 wereobtained in the same manner as in the above-mentioned Example 103 or byits analogous method.

Example 147

[0344]6-Amino-2-(2-furyl)-6′-(3-phenylpropoxy)-[3,3′]bipyridinyl-5-carbonitrile

Example 148

[0345] Ethyl4-(6′-amino-5′-cyano-2′-(2-furyl)-[3,3′]bipyridinyl-6-yloxy)butyrate

Example 149

[0346]6-Amino-6′-(3-cyanopropoxy)-2-(2-furyl)-[3,3′]bipyridinyl-5-carbonitrile

Example 150

[0347]6-Amino-6′-cyclobutylmethoxy-2-(2-furyl)-[3,3′]bipyridinyl-5-carbonitrile

Example 151

[0348]6-Amino-2-(2-furyl)-6′-(4,4,4-trifluorobutoxy)-[3,3′]bipyridinyl-5-carbonitrile

Example 152

[0349]6-Amino-2-(2-furyl)-6′-(3,4,4-trifluoro-3-butenyloxy)-[3,3′]bipyridinyl-5-carbonitrile

Example 153

[0350]6-Amino-2-(2-furyl)-6′-(3,3,3-trifluoropropoxy)-[3,3′]bipyridinyl-5-carbonitrile

Example 154

[0351] 6-Amino-6′-butoxy-2-(2-furyl)-[3,3′]bipyridinyl-5-carbonitrile

Example 155

[0352] 6-Amino-2-(2-furyl)-6′-heptyloxy-[3,3′]bipyridinyl-5-carbonitrile

Example 156

[0353]6-Amino-2-(2-furyl)-6′-(3-methylbutoxy)-[3,3′]bipyridinyl-5-carbonitrile

Example 157

[0354] 6′-Allyloxy-6-amino-2-(2-furyl)-[3,3′]bipyridinyl-5-carbonitrile

Example 158

[0355]6-Amino-6′-(3-butenyloxy)-2-(2-furyl)-[3,3′]bipyridinyl-5-carbonitrile

Example 159

[0356]6-Amino-2-(2-furyl)-6′-(4-pentenyloxy)-[3,3′]bipyridinyl-5-carbonitrile

Example 160

[0357]6-Amino-2-(2-furyl)-6′-(3-hydroxypropoxy)-[3,3′]bipyridinyl-5-carbonitrile

Example 161

[0358]6-Amino-6′-(2,3-dihydroxypropoxy)-2-(2-furyl)-[3,3′]bipyridinyl-5-carbonitrile

Example 162

[0359]6-Amino-6′-(3-fluoropropoxy)-2-(2-furyl)-[3,3′]bipyridinyl-5-carbonitrile

Example 163

[0360]6-Amino-6′-(3-chloropropoxy)-2-(2-furyl)-[3,3′]bipyridinyl-5-carbonitrile

Example 164

[0361]6-Amino-6′-(4-chlorobutoxy)-2-(2-furyl)-[3,3′]bipyridinyl-5-carbonitrile

Example 165

[0362]6-Amino-6′-(5-chloropentyloxy)-2-(2-furyl)-[3,3′]bipyridinyl-5-carbonitrile

Example 166

[0363]6-Amino-6′-cyclohexyloxy-2-(2-furyl)-[3,3′]bipyridinyl-5-carbonitrile

Example 167

[0364]6-Amino-2-(2-furyl)-6′-(2-tetrahydropyranyloxy)-[3,3′]bipyridinyl-5-carbonitrile

Example 168

[0365]6-Amino-2-(2-furyl)-6′-(2-propynyloxy)-[3,3′]bipyridinyl-5-carbonitrile

Example 169

[0366]6-Amino-6′-(2-butynyloxy)-2-(2-furyl)-[3,3′]bipyridinyl-5-carbonitrile

Example 170

[0367]6-Amino-2-(2-furyl)-6′-(3-trimethylsilanyl-2-propynyloxy)-[3,3′]bipyridinyl-5-carbonitrile

Example 171

[0368]6-Amino-6′-(6,7-dimethoxy-2-oxo-2H-chromen-4-ylmethoxy)-2-(2-furyl)-[3,3′]bipyridinyl-5-carbonitrile

Example 172

[0369]6-Amino-6′-[4-(1,3-dioxo-1,3-dihydro-2-isoindolyl)butoxy]-2-(2-furyl)-[3,3′]bipyridinyl-5-carbonitrile

Example 173

[0370]6-Amino-2-(2-furyl)-6′-[2-(1H-3-indolyl)ethoxy]-[3,3′]bipyridinyl-5-carbonitrile

Example 174

[0371]6-Amino-2-(2-furyl)-6′-(2-oxopropyl)-[3,3′]bipyridinyl-5-carbonitrile

Example 175

[0372]6-Amino-2-(2-furyl)-6′-[2-[4-(trifluoromethyl)phenyl]ethoxy]-[3,3′]bipyridinyl-5-carbonitrile

Example 176

[0373]2-Amino-4,6-di(3-fluorophenyl)-5-(4-methoxy-3-pyridyl)-3-pyridinecarbonitrile

[0374] The title compound was obtained in the same manners as inReference Examples 6 to 9 and Example 3, or by analogous methods ofthese.

[0375]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.81 (3H, s), 5.43 (2H, br s),6.41-6.46 (1H, m), 6.79-6.83 (1H, m), 6.88-7.04 (6H, m), 7.17 (1H, dt,J=2.4, 5.9 Hz), 7.29 (1H, dt, J=2.4, 5.9 Hz), 7.53-7.57 (1H, m).

Example 177

[0376]2-Amino-4,6-di(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridyl)nicotinonitrilehydrobromide

[0377] The title compound was obtained in the same manner as in Example4 or by its analogous method.

[0378]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.01 (1H, d, J=9.4 Hz), 6.86 (1H,d, J=2.4 Hz), 6.93 (1H, dd, J=2.4, 9.4 Hz), 7.04-7.24 (6H, m), 7.32-7.39(1H, m), 7.40-7.47 (1H, m).

Example 178

[0379]2-Amino-6-(2-furyl)-4-isopropoxy-5-(4-methoxy-3-pyridyl)-3-pyridinecarbonitrile

[0380] Using6-(2-furyl)-4-isopropoxy-2-oxo-1,2-dihydro-3-pyridinecarbonitrile, thetitle compound was obtained in the same manner as in Reference Examples7 to 9 and Example 3, or by its analogous method.

[0381]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.12 (6H, d, J=8.1 Hz), 3.98 (3H,s), 4.58-4.65 (1H, m), 5.44 (2H, br s), 5.97 (1H, d, J=3.3 Hz), 6.29(1H, dd, J=1.8, 3.3 Hz), 6.81 (1H, d, J=8.4 Hz), 7.37-7.43 (2H, m), 7.96(1H, d, J=1.8 Hz).

Example 179

[0382]2-Amino-6-(2-furyl)-4-hydroxy-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrilehydrobromide

[0383] Using2-amino-6-(2-furyl)-4-isopropoxy-5-(4-methoxy-3-pyridyl)-3-pyridinecarbonitrile,the title compound was obtained in the same manner as in Example 4 or byits analogous method.

[0384]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.20 (1H, d, J=3.7 Hz), 6.31 (1H,d, J=9.3 Hz), 6.61 (1H, dd, J=1.5, 3.7 Hz), 7.01 (2H, br s), 7.08 (1H,dd, J=2.4, 9.3 Hz), 7.12 (1H, d, J=2.4 Hz), 7.92 (1H, d, J=1.5 Hz),10.79 (1H, br s).

Example 180

[0385]2-Amino-6-(3-fluorophenyl)-4-isopropoxy-5-(4-methoxy-3-pyridyl)-3-pyridinecarbonitrile

[0386] The title compound was obtained in the same manner as in Examples14 to 16, Reference Examples 7 to 9 and Example 3 or by analogous methodof these.

[0387]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.13 (6H, d, J=8.1 Hz), 3.95 (3H,s), 4.44-4.58 (1H, m), 5.28 (2H, br s), 6.66 (1H, d, J=8.6 Hz),6.89-7.01 (3H, m), 7.16 (1H, dt, J=5.9, 8.0 Hz), 7.28 (1H, dd, J=1.6,8.6 Hz), 7.79-7.81 (1H, m).

Example 181

[0388]2-Amino-6-(3-fluorophenyl)-4-hydroxy-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrilehydrobromide

[0389] Using2-amino-6-(3-fluorophenyl)-4-isopropoxy-5-(4-methoxy-3-pyridyl)-3-pyridinecarbonitrile,the title compound was obtained in the same manner as in Example 4 or byits analogous method.

[0390]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.10 (1H, d, J=9.6 Hz), 6.75-6.80(1H, m), 6.89-6.93 (1H, m), 6.99 (1H, dd, J=2.7, 9.6 Hz), 7.12 (1H, d,J=7.4 Hz), 7.22-7.29 (2H, m), 7.41-7.48 (1H, m), 10.95 (1H, s).

Example 182

[0391]2-Amino-6-(3-fluorophenyl)-5-(4-methoxy-3-pyridyl)-3-pyridinecarbonitrile

[0392] The title compound was obtained in the same manners as inReference Examples 7 to 9 and Example 3 or by its analogous methods.

[0393]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.82 (3H, s), 6.71 (1H, d, J=8.4Hz), 6.99-7.04 (1H, m), 7.08-7.20 (4H, m), 7.28-7.35 (1H, m), 7.36 (1H,dd, J=2.5, 8.4 Hz), 7.95 (1H, d, J=2.5 Hz), 8.01 (1H, s);

[0394] MS m/e(ESI) 321 (MH⁺).

Example 183

[0395]2-Amino-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile

[0396] Using2-amino-6-(3-fluorophenyl)-5-(4-methoxy-3-pyridyl)-3-pyridinecarbonitrile,the title compound was obtained in the same manner as in Example 4 or byits analogous method.

[0397]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.15 (1H, d, J=8.2 Hz), 6.94-7.02(1H m), 7.04-7.28 (6H, m), 7.34-7.44 (1H, m), 7.97 (1H, s);

[0398] MS m/e(ESI) 307 (MH⁺).

Example 184

[0399]2-Amino-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile

[0400] The title compound was obtained in the same manner as inReference Examples 1 to 4 and Example 1, or by its analogous method.

[0401]¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.30 (6H, s), 6.78 (2H, s), 7.01(1H, d, J=8.0 Hz), 7.10-7.16 (1H m), 7.17-7.23 (1H, m), 7.26 (2H, s),7.29-7.35 (1H, m), 8.03 (1H, s); MS m/e(ESI) 319 (MH⁺).

[0402] The structural formulae of the title compounds of theabove-mentioned Examples 1 to 8, 10 to 76, 78, 79, 81 to 102, 105 to 175are shown below.

Example No. a b c d 1

2

3

4

5

6

7

8

Example No. R′ MS m/e(ESI,MH⁴) 10 2-Furyl 366 11 4-Cyanophenyl 401 12Phenyl 262 13 4-Methylphenyl 276 14 3-Methylphenyl 276 15 2-Methylphenyl276 16 4-Methoxyphenyl 292 17 3-Methoxyphenyl 292 18 2,4-Dimethoxyphenyl322 19 3,4-Dimethoxyphenyl 322 20 3,4,5-Trimethoxyphenyl 352 213,4-Methylenedioxyphenyl 306 22 4-Benzyloxyphenyl 368 233-Benzyloxyphenyl 368 24 4-Phenoxyphenyl 354 25 3-Ethoxyphenyl 306 264-Trifluoromethoxyphenyl 346 27 3-Trifluoromethoxyphenyl 346 284-Dimethylaminophenyl 305 29 4-Thiomethylphenyl 308 30 4-Fluorophenyl280 31 3-Fluorophenyl 280 32 2-Fluorophenyl 280 33 2,4-Difluorophenyl298 34 2,3,4,5-Pentafluoraphenyl 352 35 4-Trifluoromethylphenyl 330 363-Trifluoromethylphenyl 330 37 2-Trifluoromethylphenyl 330 383,5-Bis(trifluoromethyl)phenyl 398 39 4-Nitrophenyl 307 40 3-Nitrophenyl307 41 3-Nitro-4-methylphenyl 321 42 2-Fluoro-4-biphenylyl 356 434-Methanesulfonylphenyl 340 44 4-Methanesulfinylphenyl 324 454-Biphenylyl 338 46 3-Biphenylyl 338 47 3-Cyanophenyl 287 484-Acetylphenyl 304 49 3-Acetylphenyl 304 50 2-Acetylphenyl 304 513-Formylphenyl 290 52 2-Formylphenyl 290 53 3-Chlorophenyl 296 542-Chlorophenyl 296 55 2,4-Dichlorophenyl 330 56 3,4-Dichlorophneyl 33057 3,5-Dichlorophneyl 330 58 4-tert-Butylpheyl 318 59 1-Naphthyl 312 602-Naphthyl 312 61 2-Benzofuranyl 302 62 4-Dibenzofuranyl 352 63 3-Furyl252 64 2-Thienyl 268 65 3-Thienyl 268 66 5-Methyl-2-thienyl 282 674-Methyl-2-thienyl 282 68 5-Acetyl-2-thienyl 310 69 2-Formyl-3-thienyl296 70 3-Formyl-2-thienyl 296 71 5-Chloro-2-thienyl 302 722-Benzothiophenyl 318 73 3-Benzothiophenyl 318 74 3-Pyridyl 263 752-Pyridyl 263 76 4-Vinylphenyl 288

Example No. R R′ MS m/e (MH⁺) 78

298 (ESI) 79

310 (FAB)

[0403]

Example No. R R′ R″ R′″ MS m/e (MH⁺) 81

H H 309 (FAB) 82

H 341 (ESI) 83

H 337 (ESI) 84

Me Me 325 (ESI) 85

H 379 (ESI) 86

H 371 (ESI) 87

H 365 (ESI) 88

H 438 (ESI) 89

Me H 339 (ESI) 90

Ph H 401 (ESI) 91

H 365 (ESI) 92

H 382 (ESI) 93

H 381 (ESI) 94

H 420 (ESI) 95

H 450 (ESI) 96

H 416 (ESI) 97

H 416 (ESI) 98

H 430 (ESI) 99

H 430 (ESI) 100 

H 363 (ESI) 101 

H 383 (ESI) 102 

Et H 353 (ESI)

Example No. R MS m/e (ESI, MH⁺) 105 (CH₂)₃Ph 397 106 (CH₂)₃COOEt 393 107(CH₂)₃CN 346 108 (CH₂)₃c-C₄H₇ 347 109 (CH₂)₃CF₃ 389 110 (CH₂)₂CF═CF₂ 387111 (CH₂)₂CF₃ 375 112

335 113

377 114

349 115

319 116

333 117

347 118

337 119

353 120

339 121

355 122

369 123

383 124

375 125

377 126

369 127

332 128

317 129

331 130

389 131

497 132

480 133

422 134

335 135

465 136

355 137

380 138

381 139

369 140

369 141

385 142

385 143

380 144

373 145

373 146

373

Example No. R MS m/e (ESI, MH⁺) 147 (CH₂)₃Ph 397 148 (CH₂)₃COOEt 393 149(CH₂)₃CN 346 150 (CH₂)₃c-C₄H₇ 347 151 (CH₂)₃CF₃ 389 152 (CH₂)₂CF═CF₂ 387153 (CH₂)₂CF₃ 375 154

335 155

377 156

349 157

319 158

333 159

347 160

337 161

353 162

339 163

355 164

369 165

383 166

375 167

377 168

317 169

331 170

389 171

497 172

480 173

422 174

335 175

465

[0404] The compound of the present invention represented by the aboveformula (I) is useful as an adenosine receptor (A₁, A_(2a), A_(2b) or A₃receptor) antagonist, particularly an A_(2B) receptor antagonist. TestExamples showing the usefulness of the compound of the present inventionas a medicament are shown below.

Test Example 1 Measurement of the Ability to Bind to Adenosine A₁Receptor

[0405] A human adenosine A₁ receptor cDNA was expressed in excess inCHOK1 cells, and this membrane sample was added at a proteinconcentration of 66.7 μg/ml to, and suspended in, 20 mM HEPES buffer, pH7.4 (10 mM MgCl₂, 100 mM NaCl). To 0.45 ml of this membrane samplesuspension were added 0.025 ml of 60 nM tritium-labeledchlorocyclopentyl adenosine (³H-CCPA, from NEN Ltd.) and 0.025 ml testcompound. This mixture was left at 30° C. for 120 minutes, filteredrapidly under suction through a glass fiber filter (GF/B, from Whatman),and immediately washed twice with 5 ml of 50 mM water-cooled Tris-HClbuffer. Thereafter, the glass fiber filter was transferred to a vial, ascintillator was added thereto, and the radioactivity on the filter wasmeasured by a liquid scintillation counter. The inhibition of binding of³H-CCPA to A₁ receptor by the test compound was determined using thefollowing formula, and from this inhibition, 50% inhibitionconcentration (IC₅₀) was calculated (the following equation).

Inhibition (%)=[1-{binding in the presence of the testcompound-non-specific binding)/(total binding-non-specificbinding)}]×100

[0406] In the above formula, the total binding means ³H-CCPA-boundradioactivity in the absence of the test compound; the non-specificbinding means ³H-CCPA-bound radioactivity in the presence of 100 μM RPIA([R]-[1-methyl-2-phenylethyl] adenosine); and the binding in thepresence of the test compound means ³H-CCPA-bound radioactivity in thepresence of the test compound at predetermined concentrations. Theinhibition constant (Ki value) in the table was determined from theformula of Cheng-Prusoff.

Test Example 2 Measurement of the Ability to Bind to Adenosine A_(2a)Receptor

[0407] An experiment of inhibition of binding to adenosine A_(2a)receptor was conducted using a membrane sample (Receptor Biology Inc.)where an adenosine A_(2a) receptor cDNA was expressed in excess. Thismembrane sample was added at a protein concentration of 22.2 μg/ml to,and suspended in, 20 mM HEPES buffer, pH 7.4 (10 mM MgCl₂ and 100 mMNaCl). To 0.45 ml of this membrane sample suspension were added 0.025 mlof 500 nM tritium-labeled2-p-[2-carboxyethyl]phenetylamino-5′-N-ethylarboxyamide adenosine(³H-CGS21680, from NEN) and 0.025 ml test compound. This mixture wasleft at 25° C. for 90 minutes, filtered rapidly under suction through aglass fiber filter (GF/B, from Whatman), and immediately washed twicewith 5 ml of 50 mM water-cooled Tris-HCl buffer. Thereafter, the glassfiber filter was transferred to a vial, a scintillator was addedthereto, and the radioactivity on the filter was measured by a liquidscintillation counter. The inhibition of binding of ³H-CGS21680 toA_(2a) receptor by the test compound was determined using the followingformula, and from this inhibition, 50% inhibition concentration (IC₅₀)was calculated.

Inhibition (%)=[1-{binding in the presence of the testcompound-nonspecific binding)/(total binding-nonspecific binding)}]×100

[0408] Here, the total binding means ³H-CGS21680-bound radioactivity inthe absence of the test compound; the nonspecific binding means³H-CGS21680-bound radioactivity in the presence of 100 μM RPIA; and thebinding in the presence of the test compound means ³H-CGS21680-boundradioactivity in the absence of the test compound at predeterminedconcentrations. The inhibition constant (Ki value) in the table wasdetermined from the formula of Cheng-Prusoff.

Test Example 3 Experiment of Inhibition of NECA-stimulated Production ofcAMP in Adenosine A_(2b) Receptor-expressing Cells

[0409] CHOK1 cells where a human adenosine A_(2b) receptor had beenexpressed in excess were plated onto a 24-well plate at a density of1.5×10⁵ cells/well, cultured overnight, and used in the experiment. Thedegree of inhibitory effect of the test compound on the amount of cAMPproduced by stimulation with 30 nM 5′-N-ethylcarboxyamide adenosine(NECA from Sigma) was evaluated in terms of affinity for A_(2b)receptor. That is, the adhering cells were washed twice with 2 ml/wellKrebs-Ringer buffer solution (containing 0.1% BSA; pH 7.4) andpre-incubated for 30 minutes in a volume of 0.5 ml/well. Then, a mixedsolution containing NECA and the test compound was added in a volume of0.1 ml/well in the presence of a phosphodiesterase inhibitor Ro-20-1724(a product of RBI). After pre-incubation for 15 minutes, the reactionwas terminated with 0.1 N HCl in a volume of 300 μl/well. Measurement ofintracellular cAMP was carried out using a cAMP enzyme immunoassay kitproduced by Amersham. The inhibition of NECA-stimulated production ofcAMP by the test compound was determined using the following equation:

[0410] Inhibition (%)=[1-{(amount of cAMP in the coexistence of NECA andthe test compound-amount of CAMP in only the Krebs-Ringer buffersolution)/(amount of CAMP upon stimulation with NECA only-amount of cAMPin only the Krebs-Ringer buffer solution)}]×100

[0411] The ability of the compound according to the present invention tobind to or the ability to inhibit adenosine receptor are as follows.TABLE 1 Ki (nM) Ki (nM) IC₅₀ (nM) Test Compound A1 A2a A2b Example 1 99023 2.7       2 66 22 3.7       5 400 7 6.5

[0412] The compound according to the present invention or a salt thereofexhibited an excellent inhibitory activity on adenosine receptor.

Test Example 4 Evaluation of Defecation-Promoting Action

[0413] The defecation-promoting action of the adenosine A_(2b)receptor-inhibiting compound which was identified by measuring thebinding ability and inhibitory ability thereof to the adenosine receptorin Test Example 1, a salt thereof, a hydrate of them, or apharmaceutical composition containing it can be evaluated on the basisof the following method. That is, SD IGS rats (6 weeks-old, from CharlesRiver) were placed in cages (3 animals/cage) and preliminarily allowedfood and water ad libitum and raised for 1 week. Then, a taredwater-absorbing sheet was placed below each cage, and the animals werefasted but allowed water ad libitum throughout the experiment. After 1.5hours, the fecal pellets were recovered from each cage and observed forabnormality before the experiment. The compound suspended or dissolvedin 0.5% (w/v) methyl cellulose (MC) was orally administered in a dose of5 ml/kg. On one hand, 0.5% (w/v) MC only was orally given to the controlgroup. After administration of the compound, the rats were returned tothe cage provided with a new water-absorbing sheet, and 90 minutes afterthe administration, the fecal pellets on the water-absorbing sheet wererecovered from each cage, and the external appearance was observed, andthen counted and weighed. The number of fecal pellets is expressed pereach cage. After the fecal pellets were recovered, the water-absorbingsheet was weighed, and the weight determined by subtracting the initialweight of the water-adsorbing sheet from the weight after the experimentwas regarded as the volume of urine. TABLE 2 Example The number of fecalpellets Control —  0.50 ± 0.29 1  1 mg/kg  1.75 ± 1.03  3 mg/kg  7.25 ±1.65 10 mg/kg 22.25 ± 2.93 2  1 mg/kg  7.80 ± 0.20 10 mg/kg 18.00 ± 1.305  1 mg/kg  7.00 ± 1.23  3 mg/kg 14.25 ± 3.38

[0414] The compound according to the present invention or a salt thereofexhibited an excellent defecation-promoting action.

1. A compound represented by the formula:

(wherein R¹ represents cyano group, carboxyl group or an optionallysubstituted carbamoyl group; R²represents hydrogen atom, hydroxyl group,an optionally substituted C₁₋₆ alkoxy group, an optionally substitutedC₆₋₁₄ aromatic hydrocarbon cyclic group or an optionally substituted 5-to 14-membered aromatic heterocyclic group; and R³ and R⁴ are the sameas or different from each other and each represents a C₃₋₈ cycloalkylgroup, a C₃₋₈ cycloalkenyl group, a C₆₋₁₄ aromatic hydrocarbon cyclicgroup, a 5- to 14-membered non-aromatic heterocyclic group or a 5- to14-membered aromatic heterocyclic group which may have a substituentgroup, respectively, provided that the cases where (1) R¹ is cyanogroup, R² is 4-bromo-2-thienyl group, R³ is 3,4-dimethoxyphenyl groupand R⁴ is 2-thienyl group, (2) R¹ is cyano group, R² is hydrogen atom,and each of R³ and R⁴ is phenyl group, (3) R¹ is cyano group, R² is4-chlorophenyl group, R³ is phenyl group and R⁴ is4-(3,4-dichlorophenyl)-1-oxo-2(1H)-phthalazinyl group, (4) R¹ is cyanogroup, R² is hydrogen atom, R³ is 4-pyridyl group and R⁴ is1-piperazinyl group, (5) R¹ is cyano group, R² is hydrogen atom, R³ is4-pyridyl group and R⁴ is a 1-pyridyl group, (6) R¹ is cyano group, R²is hydrogen atom, R³ is 4-pyridyl group and R⁴ is4-diphenylmethyl-1-piperazinyl group, (7) R¹ is cyano group, R² ishydrogen atom, R³ is 4-pyridyl group and R⁴ is 4-morpholinyl group, (8)R¹ is cyano group, R² is 4-methylphenyl group, and each of R³ and R⁴ isphenyl group and (9) R¹ is cyano group, and each of R², R³ and R⁴ isphenyl group are excluded) or a salt thereof.
 2. The compound accordingto claim 1 or a salt thereof, in which R¹ is cyano group.
 3. Thecompound according to claim 1 or a salt thereof, in which R¹ is acarbamoyl group represented by the formula:

wherein R⁵ and R⁶ are the same as or different from each other and eachrepresents hydrogen atom, an optionally substituted C₁₋₆ alkyl group, anoptionally substituted C₂₋₆ alkenyl group, an optionally substitutedC₂₋₆ alkynyl group, an optionally substituted C₆₋₁₄ aromatic hydrocarboncyclic group or an optionally substituted 5- to 14-membered aromaticheterocyclic group.
 4. The compound according to claim 1 or a saltthereof, in which R² is a C₆₋₁₄ aromatic hydrocarbon cyclic group or 5-to 14-membered aromatic heterocyclic group, each of which may have asubstituent group.
 5. The compound according to claim 1 or a saltthereof, in which R² is a phenyl group, naphthyl group, pyridyl group,thienyl group or furyl group, each of which may have a substituentgroup.
 6. The compound according to claim 1 or a salt thereof, in whichR² is a phenyl group which may be substituted with a halogen atom. 7.The compound according to claim 1 or a salt thereof, in which R² ishydrogen atom.
 8. The compound according to claim 1 or a salt thereof,in which R³ and R⁴ are the same as or different from each other and eachrepresents a C₆₋₁₄ aromatic hydrocarbon cyclic group or a 5- to14-membered aromatic heterocyclic group, each of which may have asubstituent group.
 9. The compound according to claim 1 or a saltthereof, in which R³ and R⁴ are the same as or different from each otherand each represents a phenyl group, pyrrolyl group, pyridinyl group,pyridazinyl group, pyrimidinyl group, pyrazinyl group, thienyl group,thiazolyl group, furyl group, naphthyl group, quinolinyl group,isoquinolinyl group, phthalazinyl group, naphthyridinyl group, indolylgroup or isoindolyl group, each of which may have a substituent group.10. The compound according to claim 1 or a salt thereof, in which eachof R³ and R⁴ represents a phenyl group, pyridyl group, thienyl group orfuryl group which may have a substituent group, respectively.
 11. Thecompound according to claim 1 or a salt thereof, in which R³ and/or R⁴represent a 5- to 14-membered non-aromatic heterocyclic group, a C₆₋₁₄aromatic hydrocarbon cyclic group or a 5- to 14-membered aromaticheterocyclic group, each of which may be substituted with at least onegroup selected from the following substituent group a. <substituentgroup a> a group consisting of (1) hydroxyl group, (2) a halogen atom,(3) cyano group, (4) nitro group, (5) a C₁₋₆ alkyl group, C₂₋₆ alkenylgroup or C₂₋₆ alkynyl group, each of which may be substituted with atleast one group selected from (i) hydroxyl group, (ii) cyano group,(iii) halogen atom, (iv) C₁₋₆ alkylamino group, (v) di(C₁₋₆ alkyl)aminogroup, (vi) C₂₋₆ alkenylamino group, (vii) di(C₂₋₆ alkenyl)amino group,(viii) C₂₋₆ alkynylamino group, (ix) di(C₂₋₆ alkynyl)amino group, (x)N-C₁₋₆ alkyl-N-C₂₋₆ alkenylamino group, (xi) N-C₁₋₆ alkyl-N-C₂₋₆alkynylamino group, (xii) N-C₂₋₆ alkenyl-N-C₂₋₆ alkynylamino group,(xiii) aralkyloxy group, (xiv) TBDMS oxy group, (xv) C₁₋₆alkylsulfonylamino group, (xvi) C₁₋₆ alkylcarbonyloxy group, (xvii) C₂₋₆alkenylcarbonyloxy group, (xviii) C₂₋₆ alkynylcarbonyloxy group, (xix)N-C₁₋₆ alkylcarbamoyl group, (xx) N-C₂₋₆ alkenylcarbamoyl group and(xxi) N-C₁₋₆ alkynylcarbamoyl group, (6) a C₁₋₆ alkoxy group, C₂₋₆alkenyloxy group or C₂₋₆ alkynyloxy group, each of which may besubstituted with at least one group selected from (i) C₁₋₆ alkylaminogroup, (ii) aralkyloxy group and (iii) hydroxyl group, (7) a C₁₋₆alkylthio group, C₂₋₆ alkenylthio group or C₂₋₆ alkynylthio group, eachof which may be substituted with at least one group selected from (i)hydroxyl group, (ii) nitrile group, (iii) halogen atom, (iv) C₁₋₆alkylamino group, (v) aralkyloxy group, (vi) TBDMS oxy group, (vii) C₁₋₆alkylsulfonylamino group, (viii) C₁₋₆ alkylcarbonyloxy group and (ix)C₁₋₆ alkylcarbamoyl group, (8) a carbonyl group substituted with a groupselected from (i) C₁₋₆ alkoxy group, (ii) amino group, (iii) C₁₋₆alkylamino group, (iv) di(C₁₋₆ alkyl)amino group, (v) C₂₋₆ alkenylaminogroup, (vi) di (C₂₋₆ alkenyl)amino group, (vii) C₂₋₆ alkynylamino group,(vii) di(C₂₋₆ alkynyl)amino group, (viii) N-C₁₋₆ alkyl-N-C₂₋₆alkenylamino group, (ix) N-C₁₋₆ alkyl-N-C₂₋₆ alkynylamino group and (x)N-C₂₋₆ alkenyl-N-C₂₋₆ alkynylamino group, (9) an amino group which maybe substituted with one or two groups selected from (i) C₁₋₆ alkylgroup, (ii) C₂₋₆ alkenyl group, (iii) C₂₋₆ alkynyl group, (iv) C₁₋₆alkylsulfonyl group, (v) C₂₋₆ alkenylsulfonyl group, (vi) C₂₋₆alkynylsulfonyl group, (vii) C₁₋₆ alkylcarbonyl group, (viii) C₂₋₆alkenylcarbonyl group and (ix) C₂₋₆ alkynylcarbonyl group, (10) a C₁₋₆alkylsulfonyl group, (11) a C₂₋₆ alkenylsulfonyl group, (12) a C₂₋₆alkynylsulfonyl group, (13) a C₁₋₆ alkylsulfinyl group, (14) a C₂₋₆alkenylsulfinyl group, (15) a C₂₋₆ alkynylsulfinyl group, (16) formylgroup, (17) a C₃₋₈ cycloalkyl group or C₃₋₈ cycloalkenyl group, each ofwhich may be substituted with at least one group selected from (i)hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) C₁₋₆ alkylgroup, (v) C₁₋₆ alkoxy group, (vi) C₁₋₆ alkoxy-C₁₋₆ alkyl group and(vii) aralkyl group, (18) a 5- to 14-membered non-aromatic heterocyclicgroup which may be substituted with at least one group selected from (i)hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) C₁₋₆ alkylgroup, (v) C₁₋₆ alkoxy group, (vi) C₁₋₆ alkoxy-C₁₋₆ alkyl group and(vii) aralkyl group, (19) a C₆₋₁₄ aromatic hydrocarbon cyclic groupwhich may be substituted with at least one group selected from (i)hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) C₁₋₆ alkylgroup, (v) C₁₋₆ alkoxy group, (vi) C₁₋₆ alkoxy-C₁₋₆ alkyl group and(vii) aralkyl group, and (20) a 5- to 14-membered aromatic heterocyclicgroup which may be substituted with at least one group selected from (i)hydroxyl group, (ii) halogen atom, (iii) nitrile group, (iv) C₁₋₆ alkylgroup, (v) C₁₋₆ alkoxy group, (vi) C₁₋₆ alkoxy-C₁₋₆ alkyl group and(vii) aralkyl group.
 12. The compound according to claim 1 or a saltthereof, in which R³ and/or R⁴ represent a phenyl group, pyridyl group,thienyl group or furyl group, each of which may be substituted with atleast one group selected from hydroxyl group, a halogen atom, a C₁₋₆alkyl group and a C₁₋₆ alkoxy group.
 13. The compound according to claim1 or a salt thereof, in which R³ or R⁴ is a 6-oxo-1,6-dihydropyridylgroup which may have a substituent group.
 14. The compound according toclaim 1 represented by the formula:

(wherein R¹ represents cyano group, carboxyl group or an optionallysubstituted carbamoyl group; R² represents hydrogen atom, hydroxylgroup, an optionally substituted C₁₋₆ alkoxy group, an optionallysubstituted C₁₋₆ alkylthio group, an optionally substituted C₆₋₁₄aromatic hydrocarbon cyclic group or an optionally substituted 5- to14-membered aromatic heterocyclic group; R⁷ represents a group selectedfrom the following substituent group b; R⁸ represents a C₆₋₁₄ aromatichydrocarbon cyclic group or a 5- to 14-membered aromatic heterocyclicgroup which may have a substituent group, respectively; and ring Arepresents a nitrogen-containing 6-membered ring which may besubstituted with 1 to 4 groups selected from the following substituentgroup b. <substituent group b> a group consisting of hydrogen atom, ahalogen atom, hydroxyl group, nitro group, cyano group, an optionallysubstituted C₁₋₆ alkyl group, an optionally substituted C₁₋₆ alkylgroup, an optionally substituted C₂₋₆ alkenyl group, an optionallysubstituted C₂₋₆ alkynyl group, an optionally substituted C₁₋₆ alkoxygroup, an optionally substituted C₂₋₆ alkenyloxy group, an optionallysubstituted C₂₋₆ alkynyloxy group, an optionally substituted C₁₋₆alkylthio group, an optionally substituted C₂₋₆ alkenylthio group, anoptionally substituted C₂₋₆ alkynylthio group, a C₂₋₇ fatty acyl group,an optionally substituted carbamoyl group, an arylacyl group, aheteroaryl acyl group, an optionally substituted amino group, anoptionally substituted C₁₋₆ alkylsulfonyl group, an optionallysubstituted C₂₋₆ alkenylsulfonyl group, an optionally substituted C₂₋₆alkynylsulfonyl group, an optionally substituted C₁₋₆ alkylsulfinylgroup, an optionally substituted C₂₋₆ alkenylsulfinyl group, anoptionally substituted C₂₋₆ alkynylsulfinyl group, formyl group, anoptionally substituted C₃₋₈ cycloalkyl group, an optionally substitutedC₃₋₈ cycloalkenyl group, an optionally substituted 5- to 14-memberednon-aromatic heterocyclic group, an optionally substituted C₆₋₁₄aromatic hydrocarbon cyclic group and an optionally substituted 5- to14-membered aromatic heterocyclic group) or a salt thereof.
 15. Thecompound according to claim 14 or a salt thereof, in which R¹ is cyanogroup.
 16. The compound according to claim 14 or a salt thereof, inwhich R¹ is carboxyl group.
 17. The compound according to claim 14 or asalt thereof, in which R¹ is a carbamoyl group represented by theformula:

in which R⁵ and R⁶ have the same meanings as defined above.
 18. Thecompound according to claim 14 or a salt thereof, in which R² ishydrogen atom.
 19. The compound according to claim 14 or a salt thereof,in which R⁷ and the substituent groups other than R⁷ in the ring A areselected from the above-mentioned substituent group a.
 20. The compoundaccording to claim 14 or a salt thereof, in which R⁷ is hydrogen atom,an optionally substituted C₁₋₆ alkyl group, an optionally substitutedC₂₋₆ alkenyl group or an optionally substituted C₁₋₆ alkoxy group. 21.The compound according to claim 14 or a salt thereof, in which R⁸ is aphenyl group, pyridyl group, furyl group or a thienyl group, each ofwhich may have a substituent group.
 22. The compound according to claim14 or a salt thereof, in which R⁸ is a phenyl group, pyridyl group,furyl group or a thienyl group, each of which may be substituted with ahalogen atom.
 23. The compound according to claim 1, in which thecompound is any one selected from2-amino-6-(2-furyl)-5-(4-pyridyl)-3-pyridinecarbonitrile,2-amino-6-(3-fluorophenyl)-5-(4-pyridyl)-3-pyridinecarbonitrile,2-amino-6-(2-furyl)-5-(4-methoxy-3-pyridyl)-3-pyridinecarbonitrile,2-amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile,2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(2-furyl)nicotinonitrile,2-amino-6-(2-furyl)-5-(1-methyl-6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile,2-amino-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrileand2-amino-6-(3-fluorophenyl)-5-(1-methyl-6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile,or a salt thereof.
 24. A pharmaceutical composition comprising acompound represented by the formula:

(wherein R¹ represents cyano group, carboxyl group or an optionallysubstituted carbamoyl group; R² represents hydrogen atom, hydroxylgroup, an optionally substituted C₁₋₆ alkoxy group, an optionallysubstituted C₆₋₁₄ aromatic hydrocarbon cyclic group or an optionallysubstituted 5- to 14-membered aromatic heterocyclic group; and R³ and R⁴are the same as or different from each other and each represents a C₃₋₈cycloalkyl group, a C₃₋₈ cycloalkenyl group, a C₆₋₁₄ aromatichydrocarbon cyclic group, a 5- to 14-membered non-aromatic heterocyclicgroup or a 5- to 14-membered aromatic heterocyclic group which may havea substituent group, respectively, provided that the cases where (1) R¹is cyano group, R² is 4-bromo-2-thienyl group, R³ is 3,4-dimethoxyphenylgroup and R⁴ is 2-thienyl group, (2) R¹ is cyano group, R² is hydrogenatom and each of R³ and R⁴ is phenyl group, (3) R¹ is cyano group, R² is4-chloro-phenyl group, R³ is phenyl group and R⁴ is4-(3,4-dichlorophenyl)-1-oxo-2(1H)-phthalazinyl group, (4) R¹ is cyanogroup, R² is hydrogen atom, R³ is 4-pyridyl group and R⁴ is1-piperazinyl group, (5) R¹ is cyano group, R² is hydrogen atom, R³ is4-pyridyl group and R⁴ is 1-pyridyl group, (6) R¹ is cyano group, R² ishydrogen atom, R³ is 4-pyridyl group and R⁴ is4-diphenylmethyl-1-piperazinyl group, (7) R¹ is cyano group, R² ishydrogen atom, R³ is 4-pyridyl group and R⁴ is 4-morpholinyl group, (8)R¹ is cyano group, R² is 4-methylphenyl group and each of R³ and R⁴ isphenyl group, and (9) R¹ is cyano group and each of R², R³ and R⁴ isphenyl group are excluded) or a pharmacologically acceptable saltthereof and a pharmacologically acceptable carrier.
 25. The compositionaccording to claim 24, which is an agent for treating or preventing adisease to which an adenosine receptor relates.
 26. The compositionaccording to claim 24, which is an agent for treating or preventing adisease to which an adenosine A₂ receptor relates.
 27. The compositionaccording to claim 24, which is an agent for treating or preventing adisease to which an adenosine A_(2B) receptor relates.
 28. Thecomposition according to claim 24, which is an adenosine receptorantagonist.
 29. The composition according to claim 24, which is anadenosine A₂ receptor antagonist.
 30. The composition according to claim24, which is an adenosine A_(2B) receptor antagonist.
 31. Thecomposition according to claim 24, which is used for promotingdefecation.
 32. The composition according to claim 24, which is an agentfor treating, preventing or improving constipation.
 33. The compositionaccording to claim 24, in which the constipation is functionalconstipation.
 34. The composition according to claim 24, which is anagent for treating irritable bowel syndrome, constipation accompanyingirritable bowel syndrome, organic constipation, constipationaccompanying enteroparalytic ileus, constipation accompanying congenitaldigestive tract dysfunction or constipation accompanying ileus.
 35. Thecomposition according to claim 24, which is used for evacuatingintestinal tracts at the time of examination of digestive tracts orbefore and after an operation.
 36. The composition according to claim24, which is an agent for treating or preventing diabetes, diabeticcomplications, diabetic retinopathy, obesity or asthma.
 37. Thecomposition according to claim 24, which is a hypoglycemic agent, animproving agent for impaired glucose tolerance or a potentiating agentfor insulin sensitivity.
 38. The composition according to claim 24,which is a hypotensive agent, a diuretic, a therapeutic agent forosteoporosis, an anti-Parkinson's disease agent, an anti-Alzheimer'sdisease agent, a therapeutic agent for inflammatory intestinal diseasesor a therapeutic agent for Crohn's disease.
 39. Use of the compoundaccording to claim 1 or a pharmacologically acceptable salt thereof forproducing an agent for treating or preventing a disease to which anadenosine receptor relates.
 40. A method of treating or preventing adisease to which an adenosine receptor relates, by administering apharmacologically effective dose of the compound according to claim 1 ora pharmacologically acceptable salt thereof to a patient.